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Maharajan N, Cho GW, Choi JH, Jang CH. Regenerative Therapy Using Umbilical Cord Serum. In Vivo 2021; 35:699-705. [PMID: 33622862 DOI: 10.21873/invivo.12310] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Revised: 01/25/2021] [Accepted: 02/01/2021] [Indexed: 12/21/2022]
Abstract
Regenerative medicine is a branch of medicine that incorporates tissue-engineering, biomaterials, and cell therapy approaches to replace or repair damaged cells and tissues. Umbilical cord serum (UCS) is an important liquid component of cord blood, which has a reliable source of innumerable growth factors and biologically active molecules. Usually, serum can be prepared from different sources of blood. In therapeutic application, cord serum can be prepared and used in the form of eye drops for the treatment of severe dry eye diseases, ocular burns, glaucoma, persistent corneal epithelial defects and neurotrophic keratitis. In addition, cord serum combined with synthetic bio scaffold materials is used to regenerate different types of tissues including tympanic membrane regeneration, bone regeneration and nerve regeneration. Absence of animal origin viruses and bacteria, lack of xenoproteins and cost-effective features make cord serum a feasible choice as replacement of fetal bovine serum in cell culture techniques. Thus, this review emphasizes the role of cord serum in regenerative therapy and clinical uses.
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Affiliation(s)
- Nagarajan Maharajan
- Department of Biology, College of Natural Science, Chosun University, Gwangju, Republic of Korea.,Department of Life Science, BK21-Plus Research Team for Bioactive Control Technology, Chosun University, Gwangju, Republic of Korea
| | - Gwang-Won Cho
- Department of Biology, College of Natural Science, Chosun University, Gwangju, Republic of Korea.,Department of Life Science, BK21-Plus Research Team for Bioactive Control Technology, Chosun University, Gwangju, Republic of Korea
| | - Ji Hyun Choi
- Department of Obstetrics and Gynecology, Chosun University School of Medicine, Gwangju, Republic of Korea
| | - Chul Ho Jang
- Department of Otolaryngology, Chonnam National University Medical School, Gwangju, Republic of Korea
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MicroRNA-21-Enriched Exosomes as Epigenetic Regulators in Melanomagenesis and Melanoma Progression: The Impact of Western Lifestyle Factors. Cancers (Basel) 2020; 12:cancers12082111. [PMID: 32751207 PMCID: PMC7464294 DOI: 10.3390/cancers12082111] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 07/16/2020] [Accepted: 07/24/2020] [Indexed: 02/06/2023] Open
Abstract
DNA mutation-induced activation of RAS-BRAF-MEK-ERK signaling associated with intermittent or chronic ultraviolet (UV) irradiation cannot exclusively explain the excessive increase of malignant melanoma (MM) incidence since the 1950s. Malignant conversion of a melanocyte to an MM cell and metastatic MM is associated with a steady increase in microRNA-21 (miR-21). At the epigenetic level, miR-21 inhibits key tumor suppressors of the RAS-BRAF signaling pathway enhancing proliferation and MM progression. Increased MM cell levels of miR-21 either result from endogenous upregulation of melanocytic miR-21 expression or by uptake of miR-21-enriched exogenous exosomes. Based on epidemiological data and translational evidence, this review provides deeper insights into environmentally and metabolically induced exosomal miR-21 trafficking beyond UV-irradiation in melanomagenesis and MM progression. Sources of miR-21-enriched exosomes include UV-irradiated keratinocytes, adipocyte-derived exosomes in obesity, airway epithelium-derived exosomes generated by smoking and pollution, diet-related exosomes and inflammation-induced exosomes, which may synergistically increase the exosomal miR-21 burden of the melanocyte, the transformed MM cell and its tumor environment. Several therapeutic agents that suppress MM cell growth and proliferation attenuate miR-21 expression. These include miR-21 antagonists, metformin, kinase inhibitors, beta-blockers, vitamin D, and plant-derived bioactive compounds, which may represent new options for the prevention and treatment of MM.
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Short-term environmental enrichment, and not physical exercise, alleviate cognitive decline and anxiety from middle age onwards without affecting hippocampal gene expression. COGNITIVE AFFECTIVE & BEHAVIORAL NEUROSCIENCE 2019; 19:1143-1169. [DOI: 10.3758/s13415-019-00743-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
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Li A, Peng Y, Taiclet LM, Tanzi RE. Analysis of hidradenitis suppurativa-linked mutations in four genes and the effects of PSEN1-P242LfsX11 on cytokine and chemokine expression in macrophages. Hum Mol Genet 2019; 28:1173-1182. [PMID: 30544224 PMCID: PMC6423421 DOI: 10.1093/hmg/ddy414] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 11/25/2018] [Accepted: 11/27/2018] [Indexed: 12/13/2022] Open
Abstract
Hidradenitis suppurativa (HS), or acne inversa, is a chronic inflammatory skin disorder characterized clinically with acne-like lesions in apocrine gland-bearing skin, follicular occlusion and recurrent inflammation. Thirty-four unique mutations in patients with HS have been found in three genes encoding the γ-secretase complex: nicastrin (NCSTN), presenilin 1 (PSEN1), presenilin enhancer 2 (PSENEN) and in POGLUT1, an endoplasmic reticulum O-glucosyltransferase involved in Notch signaling. We have carried out a system review and have performed a functional analysis of the 34 unique reported HS-linked mutations in NCSTN, PSEN1, PSENEN and POGLUT1. We have also examined the effects of the HS-linked PSEN1-P242LfsX11 mutation on cytokine and chemokine expression in macrophages. Mutations in NCSTN are predicted to cause loss of function, to result in loss of transmembrane (TM) domain, to affect NCSTN substrate recruitment sites, to cause loss or creation of new ligand binging sites and to alter post-translational modifications and disulfide bonds. PSEN1-P242LfsX11 occurs at the opposite side of TM5 from Alzheimer's disease-linked PSEN1 mutations. All of the PSENEN mutations occur on TM regions that are predicted to disrupt membrane function. POGLUT1 mutations lead to an early termination of protein synthesis and are predicted to affect ligand binding function. In addition, PSEN1-P242LfsX11 mediates cytokine and chemokine expression and prolongs tumor necrosis factor α production on the inflammatory processes in THP-1 cells and phorbol-12-myristate-13-acetate-differentiated macrophages in response to lipopolysaccharide stimulation. These in silico analyses are instructive for functional studies of the HS-linked mutations. The PSEN1-P242LfsX11 mutation mediates cytokine and chemokine expression in macrophages.
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Affiliation(s)
- Airong Li
- Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, MassGeneral Institute for Neurodegenerative Diseases, Harvard Medical School, Charlestown, USA
| | - Yang Peng
- Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, MassGeneral Institute for Neurodegenerative Diseases, Harvard Medical School, Charlestown, USA
| | - Lauren M Taiclet
- Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, MassGeneral Institute for Neurodegenerative Diseases, Harvard Medical School, Charlestown, USA
| | - Rudolph E Tanzi
- Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, MassGeneral Institute for Neurodegenerative Diseases, Harvard Medical School, Charlestown, USA
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Moon PD, Lee JS, Kim HY, Han NR, Kang I, Kim HM, Jeong HJ. Heat-treated Lactobacillus plantarum increases the immune responses through activation of natural killer cells and macrophages on in vivo and in vitro models. J Med Microbiol 2019; 68:467-474. [DOI: 10.1099/jmm.0.000938] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Affiliation(s)
- Phil-Dong Moon
- 1 Department of Pharmacology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
- 2 Center for Converging Humanities, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Jin Soo Lee
- 1 Department of Pharmacology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Hee-Yun Kim
- 1 Department of Pharmacology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Na-Ra Han
- 1 Department of Pharmacology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Inyeong Kang
- 3 Biogenicskorea Co., Ltd., Seoul 06628, Republic of Korea
| | - Hyung-Min Kim
- 1 Department of Pharmacology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Hyun-Ja Jeong
- 4 Department of Food Science & Technology and Biochip Research Center, Hoseo University, Chungnam 31499, Republic of Korea
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Hitomi Y, Nakatani K, Kojima K, Nishida N, Kawai Y, Kawashima M, Aiba Y, Nagasaki M, Nakamura M, Tokunaga K. NFKB1 and MANBA Confer Disease Susceptibility to Primary Biliary Cholangitis via Independent Putative Primary Functional Variants. Cell Mol Gastroenterol Hepatol 2018; 7:515-532. [PMID: 30528300 PMCID: PMC6396435 DOI: 10.1016/j.jcmgh.2018.11.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Revised: 11/18/2018] [Accepted: 11/19/2018] [Indexed: 01/03/2023]
Abstract
BACKGROUND & AIMS Primary biliary cholangitis (PBC) is a chronic and cholestatic liver disease that eventually leads to cirrhosis and hepatic failure. We recently identified several susceptibility genes included NFKB1 and MANBA for PBC in the Japanese population by genome-wide association study. However, the primary functional variants in the NFKB1/MANBA region and the molecular mechanism for conferring disease susceptibility to PBC have not yet been clarified. METHODS We performed high-density association mapping based on a single-nucleotide polymorphism (SNP) imputation analysis, using data from a whole-genome sequence reference panel of 1070 Japanese individuals and the previous genome-wide association study (1389 PBC patients, 1508 healthy controls). Among SNPs (P < 5.0 × 10-7) in the NFKB1/MANBA region, putative primary functional variants and the molecular mechanism for conferring disease susceptibility to PBC were identified by in silico/in vitro functional analysis. RESULTS Among the SNPs in the NFKB1/MANBA region, rs17032850 and rs227361, which changed the binding of transcription factors lymphoid enhancer-binding factor 1 (LEF-1) and retinoid X receptor α (RXRα), respectively, were identified as putative primary functional variants that regulate gene expression. In addition, expression-quantitative trait locus data and gene editing using a clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system supported the potential role of rs17032850 and rs227361 in regulating NFKB1 and MANBA expression, respectively. CONCLUSIONS We identified independent putative primary functional variants in NFKB1/MANBA and showed the distinct molecular mechanism by which each putative primary functional variant conferred susceptibility to PBC. Our approach was useful to dissect the pathogenesis not only of PBC, but also other digestive diseases in which NFKB1/MANBA has been reported as a susceptibility locus.
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Affiliation(s)
- Yuki Hitomi
- Department of Human Genetics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan,Correspondence Address correspondence to: Yuki Hitomi, PhD, Department of Human Genetics, Graduate School of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. fax: (81) 3-5802-8619.
| | - Ken Nakatani
- Department of Human Genetics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
| | - Kaname Kojima
- Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan,Graduate School of Medicine, Tohoku University, Sendai, Japan
| | - Nao Nishida
- Department of Human Genetics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan,The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Yosuke Kawai
- Department of Human Genetics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan,Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan,Graduate School of Medicine, Tohoku University, Sendai, Japan
| | - Minae Kawashima
- Department of Human Genetics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan,Japan Science and Technology Agency, Tokyo, Japan
| | - Yoshihiro Aiba
- Clinical Research Center, National Hospital Organization, Nagasaki Medical Center, Omura, Japan
| | - Masao Nagasaki
- Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan,Graduate School of Medicine, Tohoku University, Sendai, Japan,Graduate School of Information Sciences, Tohoku University, Sendai, Japan
| | - Minoru Nakamura
- Headquarters of Primary Biliary Cholangitis (PBC) Research in National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, National Hospital Organization, Nagasaki Medical Center, Omura, Japan,Clinical Research Center, National Hospital Organization, Nagasaki Medical Center, Omura, Japan,Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Katsushi Tokunaga
- Department of Human Genetics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
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Ossetrova NI, Stanton P, Krasnopolsky K, Ismail M, Doreswamy A, Hieber KP. Comparison of Biodosimetry Biomarkers for Radiation Dose and Injury Assessment After Mixed-Field (Neutron and Gamma) and Pure Gamma Radiation in the Mouse Total-Body Irradiation Model. HEALTH PHYSICS 2018; 115:743-759. [PMID: 33289997 DOI: 10.1097/hp.0000000000000939] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
The detonation of a nuclear weapon and the occurrence of a nuclear accident represent possible mass-casualty events with significant exposure to mixed neutron and gamma radiation fields in the first few minutes after the event with the ensuing fallout, extending for miles from the epicenter, that would result primarily in photon (gamma- and/or x-ray) exposure. Circulating biomarkers represent a crucial source of information in a mass-casualty radiation exposure triage scenario. We evaluated multiple blood biodosimetry and organ-specific biomarkers for early-response assessment of radiation exposure using a mouse (B6D2F1, males and females) total-body irradiation model exposed to Co gamma rays over a broad dose range (3-12 Gy) and dose rates of either 0.6 or 1.9 Gy min and compared the results with those obtained after exposure of mice to a mixed field (neutrons and gamma rays) using the Armed Forces Radiobiology Research Institute Co gamma-ray source and TRIGA Mark F nuclear research reactor. The mixed-field studies were performed previously over a broad dose range (1.5-6 Gy), with dose rates of either 0.6 or 1.9 Gy min, and using different proportions of neutrons and gammas: either (67% neutrons + 33% gammas) or (30% neutrons + 70% gammas). Blood was collected 1, 2, 4, and 7 d after total-body irradiation. Results from Co gamma-ray studies demonstrate: (1) significant dose- and time-dependent reductions in circulating mature hematopoietic cells; (2) dose- and time-dependent changes in fms-related tyrosine kinase 3 ligand, interleukins IL-5, IL-10, IL-12, and IL-18, granulocyte colony-stimulating factors, thrombopoietin, erythropoietin, acute-phase proteins (serum amyloid A and lipopolysaccharide binding protein), surface plasma neutrophil (CD45) and lymphocyte (CD27) markers, ratio of CD45 to CD27, procalcitonin but not in intestinal fatty acid binding protein; (3) no significant differences were observed between dose-rate groups in hematological and protein profiles (fms-related tyrosine kinase 3 ligand, IL-5, IL-12, IL-18, erythropoietin, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, CD27, CD45, and ratio of CD45 to CD27) for any radiation dose at any time after exposure (p > 0.148); (4) no significant differences were observed between sex groups in hematological and protein profiles (fms-related tyrosine kinase 3 ligand, IL-18, erythropoietin, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, serum amyloid A, CD45) for any radiation dose at any time after exposure (p > 0.114); and (5) PCT level significantly increased (p < 0.008) in mice irradiated with 12 Gy on day 7 post-total-body irradiation without significant differences between groups irradiated at dose rates of either 0.6 or 1.9 Gy min (p > 0.287). Radiation-quality comparison results demonstrate that: (1) equivalent doses of pure gamma rays and mixed-field radiation do not produce equivalent biological effects, and hematopoietic syndrome occurs at lower doses of mixed-field radiation; (2) ratios of hematological and protein biomarker means in the Co study compared to mixed-field studies using 2× Co doses vs. 1× TRIGA radiation doses (i.e., 3 Gy Co vs. 1.5 Gy TRIGA) ranged from roughly 0.2 to as high as 26.5 but 57% of all ratios fell within 0.7 and 1.3; and (3) in general, biomarker results are in agreement with the relative biological effectiveness = 1.95 (Dn/Dt = 0.67) reported earlier by Armed Forces Radiobiology Research Institute scientists in mouse survival countermeasure studies.
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Affiliation(s)
- Natalia I Ossetrova
- 1Uniformed Services University, Armed Forces Radiobiology Research Institute, Scientific Research Department, 4555 South Palmer Road Bethesda, MD 20889-5648
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OK-432 Administration Inhibits Murine Allergic Rhinitis at the Induction Phase, through the Macrophage Activation with TLR2 Signaling Pathway. Med Sci (Basel) 2018; 6:medsci6040107. [PMID: 30486312 PMCID: PMC6313634 DOI: 10.3390/medsci6040107] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Revised: 11/05/2018] [Accepted: 11/05/2018] [Indexed: 11/16/2022] Open
Abstract
OK-432, a preparation of a low-virulence strain (Su) of Streptococcus pyogenes (Group A) killed by a penicillin and lyophilized, is a stiff inducer of Th1 cytokines, and exerts anti-cancer effects in tumor-bearing mice. OK-432 has been reported to consist of many bacterial components, such as peptidoglycan, M-protein, etc. However, it is yet to be ascertained which bacterial component induces T helper 1 (Th1) responses. For the last decade, Toll-like receptor (TLR) family proteins are well elucidated to play a role in recognizing bacterial components and inducing interleukin (IL)-12 from macrophages. Above all, peptidoglycan seems to be the agonist of TLR2 rather than the obverse. In our present study, the role of TLR2 for the recognition of OK-432 by macrophages and the effects of OK-432 are examined on murine allergic rhinitis model. Interestingly, results show IL-12 production by macrophages derived from TLR2 knock-out (ko) mice was significantly decreased, in comparison with that of macrophages derived from wild-type mice. Moreover, in TLR2 ko mice, no regulatory effect of OK-432 was observed on an allergic rhinitis model. These data indicate that TLR2 signaling is involved in regulating OK-432-induced anti-T helper 2 (Th2) immunity, and may offer a new prophylactic and therapeutic approach using OK-432 to downregulate allergic disorders, such as allergic rhinitis.
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Pemberton TJ, Verdu P, Becker NS, Willer CJ, Hewlett BS, Le Bomin S, Froment A, Rosenberg NA, Heyer E. A genome scan for genes underlying adult body size differences between Central African hunter-gatherers and farmers. Hum Genet 2018; 137:487-509. [PMID: 30008065 DOI: 10.1007/s00439-018-1902-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2017] [Accepted: 07/03/2018] [Indexed: 12/16/2022]
Abstract
The evolutionary and biological bases of the Central African "pygmy" phenotype, a characteristic of rainforest hunter-gatherers defined by reduced body size compared with neighboring farmers, remain largely unknown. Here, we perform a joint investigation in Central African hunter-gatherers and farmers of adult standing height, sitting height, leg length, and body mass index (BMI), considering 358 hunter-gatherers and 169 farmers with genotypes for 153,798 SNPs. In addition to reduced standing heights, hunter-gatherers have shorter sitting heights and leg lengths and higher sitting/standing height ratios than farmers and lower BMI for males. Standing height, sitting height, and leg length are strongly correlated with inferred levels of farmer genetic ancestry, whereas BMI is only weakly correlated, perhaps reflecting greater contributions of non-genetic factors to body weight than to height. Single- and multi-marker association tests identify one region and eight genes associated with hunter-gatherer/farmer status, and 24 genes associated with the height-related traits. Many of these genes have putative functions consistent with roles in determining their associated traits and the pygmy phenotype, and they include three associated with standing height in non-Africans (PRKG1, DSCAM, MAGI2). We find evidence that European height-associated SNPs or variants in linkage disequilibrium with them contribute to standing- and sitting-height determination in Central Africans, but not to the differential status of hunter-gatherers and farmers. These findings provide new insights into the biological basis of the pygmy phenotype, and they highlight the potential of cross-population studies for exploring the genetic basis of phenotypes that vary naturally across populations.
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Affiliation(s)
- Trevor J Pemberton
- Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB, Canada.
| | - Paul Verdu
- CNRS-MNHN-Université Paris Diderot, UMR 7206 Eco-Anthropologie et Ethnobiologie, Paris, France.
| | - Noémie S Becker
- Division of Evolutionary Biology, Faculty of Biology, Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany
| | - Cristen J Willer
- Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Barry S Hewlett
- Department of Anthropology, Washington State University, Vancouver, WA, USA
| | - Sylvie Le Bomin
- CNRS-MNHN-Université Paris Diderot, UMR 7206 Eco-Anthropologie et Ethnobiologie, Paris, France
| | | | | | - Evelyne Heyer
- CNRS-MNHN-Université Paris Diderot, UMR 7206 Eco-Anthropologie et Ethnobiologie, Paris, France.
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Sarjan HN, Yajurvedi HN. Chronic stress induced duration dependent alterations in immune system and their reversibility in rats. Immunol Lett 2018; 197:31-43. [PMID: 29481825 DOI: 10.1016/j.imlet.2018.02.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Revised: 01/27/2018] [Accepted: 02/19/2018] [Indexed: 12/21/2022]
Abstract
The objective was to find out whether severity of stress effects on immunity increases with duration of exposure and recovery depends on duration of exposure. Adult male rats (n = 30) were subjected to restraint (1 h) followed by forced swimming exercise (15 min) after a gap of 4 h daily for 2, 4 and 8 weeks and allowed to recover for 6 weeks after each exposure period. Exposure of rats to stress resulted in duration dependent significant decreases in leukocyte count, phagocytic indices of neutrophils, number of bone marrow stem cells and serum levels of IL-12 and increases in apoptotic index of peripheral blood mononuclear cells and serum levels of IL-10. The alterations in counts of neutrophils, total immunoglobulin content, phagocytic index, apoptotic index of peripheral blood mononuclear cells and serum levels of IL-10 returned to control levels in recovery group rats of 2 and 4 weeks exposure but not in that of 8 weeks exposure. However, alterations in number and apoptotic index of bone marrow stem cells returned to control levels in 2, 4 and 8 weeks stress recovery groups. The results for the first time reveal that increase in duration of exposure results in more severe damage in immune system and that shorter the exposure period, faster the recovery. In addition, in vitro study for the first time showed that corticosterone causes apoptosis of peripheral blood mononuclear cells and bone marrow stem cells in dose dependent manner. Hence death of leukocytes and their stem cells is the major cause of stress induced immune dysfunction.
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Affiliation(s)
- H N Sarjan
- Department of Zoology, University of Mysore, Manasagangotri, Mysore, 570 006, India.
| | - H N Yajurvedi
- Department of Zoology, University of Mysore, Manasagangotri, Mysore, 570 006, India.
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Schmidt SV, Seibert S, Walch-Rückheim B, Vicinus B, Kamionka EM, Pahne-Zeppenfeld J, Solomayer EF, Kim YJ, Bohle RM, Smola S. RIPK3 expression in cervical cancer cells is required for PolyIC-induced necroptosis, IL-1α release, and efficient paracrine dendritic cell activation. Oncotarget 2016; 6:8635-47. [PMID: 25888634 PMCID: PMC4496172 DOI: 10.18632/oncotarget.3249] [Citation(s) in RCA: 79] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2014] [Accepted: 01/28/2015] [Indexed: 11/25/2022] Open
Abstract
Previous studies have shown that cervical cancer cells only release low levels of pro-inflammatory cytokines owing to infection with human papillomaviruses. This results in low immunogenicity of the cancer cells. The viral dsRNA analog PolyIC has been suggested as a promising adjuvant for cervical cancer immunotherapy. However, little is known about the molecular requirements resulting in successful immune activation. Here, we demonstrate that stimulation of cervical cancer cells with PolyIC induced necroptotic cell death, which was strictly dependent on the expression of the receptor-interacting protein kinase RIPK3. Necroptotic cancer cells released interleukin-1α (IL-1α), which was required for powerful activation of dendritic cells (DC) to produce IL-12, a cytokine critical for anti-tumor responses. Again both, IL-1α release and DC activation, were strictly dependent on RIPK3 expression in the tumor cells. Of note, our in situ analyses revealed heterogeneous RIPK3 expression patterns in cervical squamous cell carcinomas and adenocarcinomas. In summary, our study identified a novel RIPK3-dependent mechanism that explains how PolyIC-treatment of cervical cancer cells leads to potent DC activation. Our findings suggest that the RIPK3 expression status in cervical cancer cells might critically influence the outcome of PolyIC-based immunotherapeutic approaches and should therefore be assessed prior to immunotherapy.
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Affiliation(s)
- Susanne V Schmidt
- Center for Molecular Medicine Cologne and Institute of Virology, University of Cologne, Germany
| | - Stefanie Seibert
- Institute of Virology, Saarland University, Homburg/Saar, Germany
| | | | - Benjamin Vicinus
- Institute of Virology, Saarland University, Homburg/Saar, Germany
| | | | | | | | - Yoo-Jin Kim
- Department of Pathology, Saarland University, Homburg/Saar, Germany
| | - Rainer M Bohle
- Department of Pathology, Saarland University, Homburg/Saar, Germany
| | - Sigrun Smola
- Center for Molecular Medicine Cologne and Institute of Virology, University of Cologne, Germany.,Institute of Virology, Saarland University, Homburg/Saar, Germany
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Alizadeh M, Rodriguez-Lecompte JC, Echeverry H, Crow GH, Slominski BA. Effect of yeast-derived products and distillers dried grains with solubles (DDGS) on antibody-mediated immune response and gene expression of pattern recognition receptors and cytokines in broiler chickens immunized with T-cell dependent antigens. Poult Sci 2016; 95:823-33. [PMID: 26787921 DOI: 10.3382/ps/pev449] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Accepted: 11/14/2015] [Indexed: 12/16/2022] Open
Abstract
This study evaluated the effect of yeast-derived products on innate and antibody mediated immune response in broiler chickens following immunization with sheep red blood cells (SRBC) and bovine serum albumin (BSA). One-day-old male broiler chickens (Ross-308) were randomly assigned to 6 dietary treatments of 9 replicate cages of 5 birds each per treatment. Dietary treatments consisted of a Control diet without antibiotic, and diets containing 11 mg/kg of virginiamycin, 0.25% of yeast cell wall (YCW), 0.2% of a commercial product Maxi-Gen Plus containing processed yeast and nucleotides, 0.05% of nucleotides, or a diet containing 10% of DDGS. On days 21 and 28 post-hatching, 5 birds per treatment were immunized intramuscularly with both SRBC and BSA. One week after each immunization, blood samples were collected. Serum samples were analyzed by hemagglutination test for antibody response to SRBC, and by ELISA for serum IgM and IgG response to BSA. On d 35, 5 birds per treatment were euthanized and the tissue samples from the cecal tonsils were collected to assess the gene expression of toll-like receptors TLR2b, TLR4, and TLR21, monocyte mannose receptor (MMR), and cytokines IL-10, IL-13, IL-4, IL-12p35, and IFN-γ. The results for gene expression analysis demonstrated that the diet supplemented with YCW increased the expression of TLR2b and T-helper type 2 cytokines IL-10, IL-4, and IL-13 relative to the Control; and the expression of TLR4 and IL-13 was upregulated in the nucleotide-containing diet. However, the diets containing antibiotics or Maxi-Gen Plus downregulated the expression of IFN-γ compared to the control. The primary antibody response to SRBC was not affected by diets. However, the diet containing YCW increased the secondary antibody response to SRBC compared to the antibiotic treatment. Neither primary nor secondary IgG and IgM response against BSA were affected by diets. In conclusion, supplementation of the diet with YCW stimulated Th2 cell-mediated immune response indicating the immunomodulatory activities of these products following immunization with non-inflammatory antigens.
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Affiliation(s)
- M Alizadeh
- Department of Animal Science, University of Manitoba, Winnipeg, MB, Canada R3T 2N2
| | - J C Rodriguez-Lecompte
- Department of Pathology and Microbiology, Atlantic Veterinary College, University of Prince Edward Island, PE, Canada C1A 4P3
| | - H Echeverry
- Department of Animal Science, University of Manitoba, Winnipeg, MB, Canada R3T 2N2
| | - G H Crow
- Department of Animal Science, University of Manitoba, Winnipeg, MB, Canada R3T 2N2
| | - B A Slominski
- Department of Animal Science, University of Manitoba, Winnipeg, MB, Canada R3T 2N2
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13
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Tan A, Gao Y, Yao Z, Su S, Jiang Y, Xie Y, Xian X, Mo Z. Genetic variants in IL12 influence both hepatitis B virus clearance and HBV-related hepatocellular carcinoma development in a Chinese male population. Tumour Biol 2015; 37:6343-8. [PMID: 26631030 DOI: 10.1007/s13277-015-4520-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Accepted: 11/25/2015] [Indexed: 12/14/2022] Open
Abstract
IL12 plays a major role not only in inducing appropriate immune responses against viral infections (including HBV) but also in the antitumor immune response. This study was conducted to investigate the relationships of genetic variants in IL12 with hepatitis B virus (HBV) clearance and development of HBV-related hepatocellular carcinoma (HCC). We genotyped three single nucleotide polymorphisms (SNPs) of the IL12A (rs568406 and rs2243115) and IL12B (rs3212227) in 395 HBV-positive HCC patients, 293 persistent HBV carriers and 686 subjects with HBV natural clearance from southern China, using the improved multiplex ligase detection reaction (iMLDR) method. Logistic regression analysis adjusted for age, smoking, and alcohol consumption status showed that rs568408 variant genotypes were significantly associated with host HBV-related HCC risk when compared with persistent HBV carriers, and carriers of the GA + AA genotype decreased the HCC risk in comparison with GG carriers (adjusted OR = 0.53, 95 % CI 0.35-0.80, P = 0.002). No relationships between the rs2243115 and rs3212227 SNPs and HCC risk were observed (all P > 0.05). Besides, rs568408 showed an approaching significant effect on susceptibility to HBV persistent infection (adjusted OR = 1.34, 95 % CI 0.99-1.81, P = 0.057 in dominant genetic models). Furthermore, the TG haplotype was observed to be associated with a significantly increased risk of HBV-related HCC (OR = 1.42, 95 % CI 1.10-1.83, P = 0.006), while TA haplotype was associated with a decreased risk of HBV-related HCC (OR = 0.61, 95 % CI 0.45-0.83, P = 0.002). Our results reveal that the IL12A rs568408 variant may be a marker SNP for risk of both HBV clearance and HBV-related HCC development.
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Affiliation(s)
- Aihua Tan
- Department of chemotherapy, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China.,Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Yong Gao
- Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Ziting Yao
- Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Shining Su
- TalentCloud Information Technology Ltd, Nanning, Guangxi, 530021, China
| | - Yonghua Jiang
- Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Yuanliang Xie
- Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Xiaoying Xian
- Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Zengnan Mo
- Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi, 530021, China.
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14
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Boyerinas B, Jochems C, Fantini M, Heery CR, Gulley JL, Tsang KY, Schlom J. Antibody-Dependent Cellular Cytotoxicity Activity of a Novel Anti-PD-L1 Antibody Avelumab (MSB0010718C) on Human Tumor Cells. Cancer Immunol Res 2015; 3:1148-1157. [PMID: 26014098 DOI: 10.1158/2326-6066.cir-15-0059] [Citation(s) in RCA: 365] [Impact Index Per Article: 36.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Accepted: 05/19/2015] [Indexed: 12/18/2022]
Abstract
Several anti-PD-1/PD-L1 monoclonal antibodies (mAb) are currently providing evidence of clinical benefit in subsets of cancer patients. The mode of action of these mAbs is to inhibit PD-1 on immune cells interacting with PD-L1 on tumor cells. These mAbs are either designed or engineered to eliminate antibody-dependent cell-mediated cytotoxicity (ADCC), which, however, has been implicated as an important mechanism in several highly effective mAb-mediated cancer therapies. A fully human anti-PD-L1 mAb would potentially be able to block PD-1/PD-L1 interactions and also mediate the ADCC lysis of tumor cells. MSB0010718C (designated avelumab) is a fully human IgG1 anti-PD-L1 mAb. The studies reported here demonstrate (i) the ability of avelumab to lyse a range of human tumor cells in the presence of PBMC or NK effectors; (ii) IFNγ can enhance tumor cell PD-L1 expression and, in some cases, enhance ADCC tumor cell lysis; (iii) purified NK cells are potent effectors for avelumab; (iv) similar levels of avelumab-mediated ADCC lysis of tumor cells are seen using purified NK as effectors from either healthy donors or cancer patients; (v) very low levels of avelumab-mediated lysis are seen using whole PBMCs as targets; this finding complements results seen in analyses of PBMC subsets of patients receiving avelumab; and (vi) the addition of IL12 to NK cells greatly enhances avelumab-mediated ADCC. These studies thus provide an additional mode of action for an anti-PD-L1 mAb and support the rationale for further studies to enhance avelumab-mediated ADCC activity.
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MESH Headings
- Antibodies, Monoclonal/pharmacology
- Antibodies, Monoclonal, Humanized
- Antibody-Dependent Cell Cytotoxicity/drug effects
- Antibody-Dependent Cell Cytotoxicity/genetics
- Antibody-Dependent Cell Cytotoxicity/immunology
- Antineoplastic Agents/pharmacology
- B7-H1 Antigen/antagonists & inhibitors
- B7-H1 Antigen/genetics
- B7-H1 Antigen/metabolism
- Biomarkers, Tumor
- Cell Line, Tumor
- Cell Membrane/metabolism
- Gene Expression
- Genotype
- Humans
- Interferon-gamma/metabolism
- Interferon-gamma/pharmacology
- Interleukin-12/pharmacology
- Killer Cells, Natural/drug effects
- Killer Cells, Natural/immunology
- Killer Cells, Natural/metabolism
- Leukocytes, Mononuclear/drug effects
- Leukocytes, Mononuclear/immunology
- Leukocytes, Mononuclear/metabolism
- Neoplasms/genetics
- Neoplasms/immunology
- Neoplasms/metabolism
- Receptors, IgG/genetics
- T-Lymphocytes, Cytotoxic/immunology
- T-Lymphocytes, Cytotoxic/metabolism
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Affiliation(s)
- Benjamin Boyerinas
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Caroline Jochems
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Massimo Fantini
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Christopher R Heery
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - James L Gulley
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland
| | - Kwong Yok Tsang
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Jeffrey Schlom
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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15
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Peng Q, Li S, Lao X, Chen Z, Li R, Qin X. Interleukin-12B+1188A/C polymorphism contributes to increased hepatocellular carcinoma susceptibility: evidence from a meta-analysis. Clin Res Hepatol Gastroenterol 2014; 38:735-43. [PMID: 25445750 DOI: 10.1016/j.clinre.2014.09.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2014] [Revised: 08/30/2014] [Accepted: 09/08/2014] [Indexed: 02/04/2023]
Abstract
BACKGROUND Interleukin-12 (IL-12) is a multifunctional cytokine that induces interferon (IFN)-γ secretion and plays an important role in antitumor immunity. The IL-12B +1188A/C polymorphism was found to correlate with a decreased cytokine production and/or activity, which may lead to increased susceptibility to cancers including hepatocellular carcinoma (HCC). Previous epidemiological studies investigating the association between IL-12B +1188A/C polymorphism and HCC risk reported inconsistent results. We performed a meta-analysis to derive a precise estimation of the association. METHODS All studies published up to July 2014 on the association between IL-12B +1188A/C polymorphism and HCC risk were identified by searching electronic databases including PubMed, Embase, Cochrane library, and Chinese Biomedical Literature database (CBM). Data were extracted by two independent authors and the odds ratios (ORs) together with corresponding 95% confidence intervals (CIs) were used to assess the association between IL-12B +1188A/C polymorphism and HCC risk. RESULTS Five studies with 1864 cases and 2077 controls were included in the meta-analysis. We observed that the IL-12B +1188A/C polymorphism was significantly correlated with increased HCC risk when all studies were pooled into the meta-analysis (CC vs. AA: OR=1.306, 95% CI 1.063-1.606, P=0.011; AC vs. AA: OR=1.193, 95% CI 1.014-1.405, P=0.034; CC+AC vs. AA: OR=1.260, 95% CI 1.098-1.445, P=0.001). In subgroup analyses by ethnicity, source of control, and study quality, significant increased HCC risk was found in Asians, hospital-based studies, and high quality studies. CONCLUSIONS The present meta-analysis suggests that the IL-12B+1188A/C polymorphism is a low-penetrant risk factor for HCC development, especially among Asians. Further large and well-designed studies are needed to confirm this association.
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Affiliation(s)
- Qiliu Peng
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Shan Li
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Xianjun Lao
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Zhiping Chen
- Department of Occupational Health and Environmental Health, School of Public Health at Guangxi Medical University, Nanning, Guangxi, China
| | - Ruolin Li
- Department of Medicine Research, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Xue Qin
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
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16
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Hu J, Hu Y, Chen S, Dong C, Zhang J, Li Y, Yang J, Han X, Zhu X, Xu G. Role of activated macrophages in experimental Fusarium solani keratitis. Exp Eye Res 2014; 129:57-65. [PMID: 25447809 DOI: 10.1016/j.exer.2014.10.014] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2014] [Revised: 07/31/2014] [Accepted: 10/13/2014] [Indexed: 10/24/2022]
Abstract
Macrophages under the conjunctival tissue are the first line defender cells of the corneas. Elimination of these cells would lead to aggravation of fungal keratitis. To determine how the course of fungal keratitis would be altered after the activation of these macrophages, a murine model was achieved by intrastromal instillation of latex beads before the corneas were infected with Fusarium solani. The keratitis was observed and clinically scored daily. Infected corneas were homogenized for colony counts. The levels of the IL-12, IL-4, MPO, MIF and iNOS cytokines were measured in the corneas using real-time polymerase chain reactions and enzyme-linked immunosorbent assays. CD3+, CD4+ and CD8+ lymphocytes in the corneas, submaxillary lymph nodes and peripheral blood were detected using immunohistochemistry and flow cytometry, respectively. The latex bead-treated mice exhibited aggravated keratitis. Substantially increased macrophage and polymorphonuclear leukocyte infiltration was detected in the corneas, although few colonies were observed. There was a marked increase in the IL-12, IL-4, MPO, MIF and iNOS expression in the corneas. The numbers of CD3+, CD4+ and CD8+ lymphocytes and the CD4+/CD8+ ratio were significantly enhanced in the corneas and submaxillary lymph nodes. However, the number of CD4+ lymphocytes was decreased in the peripheral blood, while the number of CD8+ lymphocytes increased. Collectively, our data demonstrate that the activation of macrophages in the cornea may cause an excessive immune response. Macrophages appear to play a critical role in regulating the immune response to corneal infections with F. solani.
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Affiliation(s)
- Jianzhang Hu
- The Eye Center of the First Affiliated Hospital of Fujian Medical University, Fujian Eye Institute, 20 Chazhong Road, Fuzhou 350005, China
| | - Yingfeng Hu
- The Eye Center of the First Affiliated Hospital of Fujian Medical University, Fujian Eye Institute, 20 Chazhong Road, Fuzhou 350005, China
| | - Shikun Chen
- The Eye Center of the First Affiliated Hospital of Fujian Medical University, Fujian Eye Institute, 20 Chazhong Road, Fuzhou 350005, China
| | - Chenhuan Dong
- The Eye Center of the First Affiliated Hospital of Fujian Medical University, Fujian Eye Institute, 20 Chazhong Road, Fuzhou 350005, China
| | - Jingjin Zhang
- The Eye Center of the First Affiliated Hospital of Fujian Medical University, Fujian Eye Institute, 20 Chazhong Road, Fuzhou 350005, China
| | - Yanling Li
- The Eye Center of the First Affiliated Hospital of Fujian Medical University, Fujian Eye Institute, 20 Chazhong Road, Fuzhou 350005, China
| | - Juan Yang
- The Eye Center of the First Affiliated Hospital of Fujian Medical University, Fujian Eye Institute, 20 Chazhong Road, Fuzhou 350005, China
| | - Xiaoli Han
- The Eye Center of the First Affiliated Hospital of Fujian Medical University, Fujian Eye Institute, 20 Chazhong Road, Fuzhou 350005, China
| | - Xuejun Zhu
- The Eye Center of the First Affiliated Hospital of Fujian Medical University, Fujian Eye Institute, 20 Chazhong Road, Fuzhou 350005, China
| | - Guoxing Xu
- The Eye Center of the First Affiliated Hospital of Fujian Medical University, Fujian Eye Institute, 20 Chazhong Road, Fuzhou 350005, China.
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17
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Sarlos P, Kovesdi E, Magyari L, Banfai Z, Szabo A, Javorhazy A, Melegh B. Genetic update on inflammatory factors in ulcerative colitis: Review of the current literature. World J Gastrointest Pathophysiol 2014; 5:304-21. [PMID: 25133031 PMCID: PMC4133528 DOI: 10.4291/wjgp.v5.i3.304] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Revised: 03/19/2014] [Accepted: 07/12/2014] [Indexed: 02/06/2023] Open
Abstract
Ulcerative colitis (UC) is one of the main types of inflammatory bowel disease, which is caused by dysregulated immune responses in genetically predisposed individuals. Several genetic factors, including interleukin and interleukin receptor gene polymorphisms and other inflammation-related genes play central role in mediating and modulating the inflammation in the human body, thereby these can be the main cause of development of the disease. It is clear these data are very important for understanding the base of the disease, especially in terms of clinical utility and validity, but summarized literature is exiguous for challenge health specialist that can used in the clinical practice nowadays. This review summarizes the current literature on inflammation-related genetic polymorphisms which are associated with UC. We performed an electronic search of Pubmed Database among publications of the last 10 years, using the following medical subject heading terms: UC, ulcerative colitis, inflammation, genes, polymorphisms, and susceptibility.
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18
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Takahashi A, Kimura F, Yamanaka A, Takebayashi A, Kita N, Takahashi K, Murakami T. The FOXL2 mutation (c.402C>G) in adult-type ovarian granulosa cell tumors of three Japanese patients: clinical report and review of the literature. TOHOKU J EXP MED 2014; 231:243-50. [PMID: 24257635 DOI: 10.1620/tjem.231.243] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Adult-type granulosa cell tumor (AGCT) is a rare class of malignant ovarian tumor with unique features, characterized by slow growth, late recurrence, relatively good prognosis and unified cause in almost all patients. The forkhead box L2 (FOXL2) gene encodes an essential transcription factor in the ovary. FOXL2 is important in female sex determination, follicle recruitment, and granulosa cell development. About 70-97% of AGCTs were reported to carry a somatic mutation c.402C>G (C134W) in the FOXL2 gene. However, it is unknown whether AGCTs of Japanese patients harbor the FOXL2 c.402C>G mutation. Here, we report a mutational analysis of the FOXL2 gene in four Japanese patients with AGCTs, and we review the literature to determine the precise incidence of FOXL2 mutations in AGCTs. All four patients were analyzed by immunohistochemistry for FOXL2. Genomic DNA was extracted from paraffin-embedded tissues, and was analyzed to detect the c.402C>G mutation in FOXL2 by direct sequencing. All tumors were stained with FOXL2. Three of the four tumors harbor the c.402C>G mutation. Based on the literature review, FOXL2 immunostaining is a highly specific marker for sex cord-stromal tumors (SCSTs), but it is not specific for AGCTs, one subtype of SCSTs. We identified 340 patients with the FOXL2 mutation (c.402C>G) and determined that the incidence of the mutation is 91.9% in AGCT patients. Therefore, this FOXL2 mutation is specific to AGCTs in the ovary and is useful for diagnosis of this disease.
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Affiliation(s)
- Akimasa Takahashi
- Department of Obstetrics and Gynecology, Shiga University of Medical Science
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19
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Gokhale MS, Vainstein V, Tom J, Thomas S, Lawrence CE, Gluzman-Poltorak Z, Siebers N, Basile LA. Single low-dose rHuIL-12 safely triggers multilineage hematopoietic and immune-mediated effects. Exp Hematol Oncol 2014; 3:11. [PMID: 24725395 PMCID: PMC3991894 DOI: 10.1186/2162-3619-3-11] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2013] [Accepted: 04/01/2014] [Indexed: 01/12/2023] Open
Abstract
Background Recombinant human interleukin 12 (rHuIL-12) regulates hematopoiesis and cell-mediated immunity. Based on these hematopoietic and immunomodulatory activities, a recombinant human IL-12 (rHuIL-12) is now under development to address the unmet need for a medical countermeasure against the hematopoietic syndrome of the acute radiation syndrome (HSARS) that occurs in individuals exposed to lethal radiation, and also to serve as adjuvant therapy that could provide dual hematopoietic and immunotherapeutic benefits in patients with cancer receiving chemotherapy. We sought to demonstrate in healthy subjects the safety of rHuIL-12 at single, low doses that are appropriate for use as a medical countermeasure for humans exposed to lethal radiation and as an immunomodulatory anti-cancer agent. Methods Two placebo-controlled, double-blinded studies assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of rHuIL-12. The first-in-human (FIH) dose-escalation study randomized subjects to single subcutaneous injections of placebo or rHuIL-12 at 2, 5, 10, and 20 μg doses. Due to toxicity, dose was reduced to 15 μg and then to 12 μg. The phase 1b expansion study randomized subjects to the highest safe and well tolerated dose of 12 μg. Results Thirty-two subjects were enrolled in the FIH study: 4 active and 2 placebo at rHuIL-12 doses of 2, 5, 10, 12, and 15 μg; 1 active and 1 placebo at 20 μg. Sixty subjects were enrolled in the expansion study: 48 active and 12 placebo at 12 μg dose of rHuIL-12. In both studies, the most common adverse events (AEs) related to rHuIL-12 were headache, dizziness, and chills. No immunogenicity was observed. Elimination of rHuIL-12 was biphasic, suggesting significant distribution into extravascular spaces. rHuIL-12 triggered transient changes in neutrophils, platelets, reticulocytes, lymphocytes, natural killer cells, and CD34+ hematopoietic progenitor cells, and induced increases in interferon-γ and C-X-C motif chemokine 10. Conclusion A single low dose of rHuIl-12 administered subcutaneously can elicit hematological and immune-mediated effects without undue toxicity. The safety and the potent multilineage hematopoietic/immunologic effects triggered by low-dose rHuIL-12 support the development of rHuIL-12 both as a radiation medical countermeasure and as adjuvant immunotherapy for cancer. Trial registration ClinicalTrials.gov: NCT01742221
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Affiliation(s)
| | | | | | | | | | | | | | - Lena A Basile
- Neumedicines Inc, 133 North Altadena Drive, Suite 310, 91107-7342 Pasadena, CA, USA.
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20
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Magyari L, Kovesdi E, Sarlos P, Javorhazy A, Sumegi K, Melegh B. Interleukin and interleukin receptor gene polymorphisms in inflammatory bowel diseases susceptibility. World J Gastroenterol 2014; 20:3208-22. [PMID: 24695754 PMCID: PMC3964393 DOI: 10.3748/wjg.v20.i12.3208] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 12/20/2013] [Accepted: 02/20/2014] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), represents a group of chronic inflammatory disorders caused by dysregulated immune responses in genetically predisposed individuals. Genetic markers are associated with disease phenotype and long-term evolution, but their value in everyday clinical practice is limited at the moment. IBD has a clear immunological background and interleukins play key role in the process. Almost 130 original papers were revised including meta-analysis. It is clear these data are very important for understanding the base of the disease, especially in terms of clinical utility and validity, but text often do not available for the doctors use these in the clinical practice nowadays. We conducted a systematic review of the current literature on interleukin and interleukin receptor gene polymorphisms associated with IBD, performing an electronic search of PubMed Database from publications of the last 10 years, and used the following medical subject heading terms and/or text words: IBD, CD, UC, interleukins and polymorphisms.
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21
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Singh M, Ramos I, Asafu-Adjei D, Quispe-Tintaya W, Chandra D, Jahangir A, Zang X, Aggarwal BB, Gravekamp C. Curcumin improves the therapeutic efficacy of Listeria(at)-Mage-b vaccine in correlation with improved T-cell responses in blood of a triple-negative breast cancer model 4T1. Cancer Med 2013; 2:571-82. [PMID: 24156030 PMCID: PMC3799292 DOI: 10.1002/cam4.94] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2012] [Revised: 04/04/2013] [Accepted: 04/23/2013] [Indexed: 12/13/2022] Open
Abstract
Success of cancer vaccination is strongly hampered by immune suppression in the tumor microenvironment (TME). Interleukin (IL)-6 is particularly and highly produced by triple-negative breast cancer (TNBC) cells, and has been considered as an important contributor to immune suppression in the TME. Therefore, we hypothesized that IL-6 reduction may improve efficacy of vaccination against TNBC cancer through improved T-cell responses. To prove this hypothesis, we investigated the effect of curcumin, an inhibitor of IL-6 production, on vaccination of a highly attenuated Listeria monocytogenes (Listeriaat), encoding tumor-associated antigens (TAA) Mage-b in a TNBC model 4T1. Two therapeutic vaccination strategies with Listeriaat-Mage-b and curcumin were tested. The first immunization strategy involved all Listeriaat-Mage-b vaccinations and curcumin after tumor development. As curcumin has been consumed all over the world, the second immunization strategy involved curcumin before and all therapeutic vaccinations with Listeriaat-Mage-b after tumor development. Here, we demonstrate that curcumin significantly improves therapeutic efficacy of Listeriaat-Mage-b with both immunization strategies particularly against metastases in a TNBC model (4T1). The combination therapy was slightly but significantly more effective against the metastases when curcumin was administered before compared to after tumor development. With curcumin before tumor development in the combination therapy, the production of IL-6 was significantly decreased and IL-12 increased by myeloid-derived suppressor cells (MDSC), in correlation with improved CD4 and CD8 T-cell responses in blood. Our study suggests that curcumin improves the efficacy of Listeriaat-Mage-b vaccine against metastases in TNBC model 4T1 through reversal of tumor-induced immune suppression. This study is focused on improving cancer vaccination by reducing immune suppression. Here we demonstrate that curcumin improves vaccine efficacy of Listeria-Mage-b by converting myeloid-derived suppressor cells into an immune stimulating phenotype, that is, through reducing IL-6 and increasing IL-12 production, in correlation with improved T cell responses and a dramatic reduction in the number of metastases. The novel results of this study may be a platform for improvement of other cancer vaccines by curcumin.
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Affiliation(s)
- Manisha Singh
- Department of Microbiology and Immunology, Albert Einstein College of Medicine 1300 Morris Park Avenue, Bronx, New York, 10461
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22
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Kim SB, Chang BY, Han SB, Hwang BY, Kim SY, Lee MK. A new phenolic glycoside from Cnidium monnieri fruits. Nat Prod Res 2013; 27:1945-8. [PMID: 23721280 DOI: 10.1080/14786419.2013.796467] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
A new phenolic glycoside, methylpicraquassioside B (6), together with nine known glycosides, cnidioside A (1), cnidioside B (2), picraquassioside A (3), methylpicraquassioside A (4), picraquassioside B (5), xanthotoxol-8-β-glucoside (7), 5-methoxy-xanthotoxol-8-β-glucoside (8), 8-methoxy-xanthotoxol-5-β-glucoside (9) and marmesinin (10) were isolated from n-BuOH-soluble fraction of Cnidium monnieri fruits. All the isolated compounds, however, exerted little immunomodulatory effect in RAW 264.7 cells.
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Affiliation(s)
- Seon Beom Kim
- a College of Pharmacy, Chungbuk National University , Cheongju Chungbuk 361-763 , South Korea
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23
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Association of IL27 gene polymorphisms and HBV-related hepatocellular carcinoma risk in a Chinese population. INFECTION GENETICS AND EVOLUTION 2013; 16:1-4. [PMID: 23395794 DOI: 10.1016/j.meegid.2013.01.015] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/30/2012] [Revised: 01/26/2013] [Accepted: 01/29/2013] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND OBJECTIVE Hepatocellular carcinoma (HCC) is multifactorial, and the genetic background may be a crucial etiologic factor. Interleukin-27 (IL-27) is a novel IL-12 family member which plays an important role in antitumor immunity. Mutations in the IL27 gene may lead to altered cytokine production and/or activity and thus modulate individual's susceptibility to HCC. In this study, we investigated the association between IL27 gene polymorphisms and HBV-related diseases risk in a Chinese population. METHODS Studied subjects were divided into four groups: 112 patients with chronic hepatitis B (CHB), 65 patients with hepatitis B virus (HBV)-related liver cirrhosis (LC), 107 patients with HBV-related HCC, and 105 healthy controls. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) strategy and polymerase chain reaction-sequence specific primer (PCR-SSP) strategy were used to detect IL27 gene -964A/G and 2905T/G polymorphisms, respectively. DNA sequencing was used to validate genotype results. RESULTS There were no significant differences in the genotype and allele frequencies of IL27 gene polymorphisms between the groups of patients and healthy controls. Furthermore, no association was found between the distributions of the haplotypes and HCC risk. CONCLUSION These findings indicate that the genetic variants in IL27 gene may not contribute to HCC development. Further studies with large sample size should be conducted to validate this association.
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Avouac J, Fürnrohr BG, Tomcik M, Palumbo K, Zerr P, Horn A, Dees C, Akhmetshina A, Beyer C, Distler O, Schett G, Allanore Y, Distler JHW. Inactivation of the transcription factor STAT-4 prevents inflammation-driven fibrosis in animal models of systemic sclerosis. ACTA ACUST UNITED AC 2013; 63:800-9. [PMID: 21360510 DOI: 10.1002/art.30171] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE The transcription factor STAT-4 has recently been identified as a genetic susceptibility factor in systemic sclerosis (SSc) and other autoimmune diseases. The aim of this study was to investigate the contribution of STAT-4 in the development of a fibrotic phenotype in 2 different mouse models of experimental dermal fibrosis. METHODS STAT-4-deficient (stat4(-/-) ) mice and their wild-type littermates (stat4(+/+) ) were injected with bleomycin or NaCl. Infiltrating leukocytes, T cells, B cells, and monocytes were quantified in the lesional skin of stat4(-/-) and stat4(+/+) mice. Inflammatory and profibrotic cytokines were measured in sera and lesional skin samples from stat4(-/-) and stat4(+/+) mice. The outcome of mice lacking STAT-4 was also investigated in the tight skin 1 (TSK-1) mouse model. RESULTS Stat4(-/-) mice were protected against bleomycin-induced dermal fibrosis, with a reduction in dermal thickening (mean ± SEM 65 ± 3% decrease; P = 0.03), hydroxyproline content (68 ± 5% decrease; P = 0.02), and myofibroblast counts (71 ± 6% decrease; P = 0.005). Moreover, the number of infiltrating leukocytes, especially T cells, was significantly decreased in the lesional skin of stat4(-/-) mice (mean ± SEM 63 ± 5% reduction in T cell count; P = 0.02). Stat4(-/-) mice also displayed decreased levels of inflammatory cytokines such as tumor necrosis factor α, interleukin-6 (IL-6), IL-2, and interferon-γ in lesional skin. Consistent with a primary role of STAT-4 in inflammation, STAT-4 deficiency did not ameliorate fibrosis in TSK-1 mice. CONCLUSION The results of this study demonstrate that the transcription factor STAT-4 exerts potent profibrotic effects by controlling T cell activation and proliferation and cytokine release. These findings confirm the results of genetics studies on the role of STAT-4 in the development of SSc.
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Affiliation(s)
- Jérôme Avouac
- University of Erlangen-Nuremberg, Erlangen, Germany.
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25
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Kim SB, Chang BY, Jo YH, Lee SH, Han SB, Hwang BY, Kim SY, Lee MK. Macrophage activating activity of pyrrole alkaloids from Morus alba fruits. JOURNAL OF ETHNOPHARMACOLOGY 2013; 145:393-6. [PMID: 23164765 DOI: 10.1016/j.jep.2012.11.007] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/14/2012] [Revised: 11/02/2012] [Accepted: 11/05/2012] [Indexed: 05/06/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The fruits of Morus alba have been traditionally used as a tonic to enhance immune responses. MATERIALS AND METHODS The macrophage activating constituents of Morus alba fruits were purified using various column chromatography techniques. The structures of isolated compounds were determined on the basis of spectroscopic data interpretation such as 1D and 2D NMR analysis. The macrophage activating activities of isolated compounds were evaluated by measuring the production of nitric oxide, TNF-α and IL-12 in RAW 264.7 cells. The phagocytic activity was also evaluated. RESULTS Five pyrrole alkaloids, 5-(hydroxymethyl)-1H-pyrrole-2-carboxaldehyde (1), 2-formyl-1H-pyrrole-1-butanoic acid (2), 2-formyl-5-(hydroxymethyl)-1H-pyrrole-1-butanoic acid (3), 2-formyl-5-(methoxymethyl)-1H-pyrrole-1-butanoic acid (4) and Morrole A (5) were isolated from the fruits of Morus alba. Morrole A (5) is first reported in nature and other pyrrole alkaloids (1-4) are first reported from Morus species. Among the isolated compounds, compounds 3 and 4 significantly activated macrophage activity by the enhancement of nitric oxide, TNF-α and IL-12 production, and the stimulation of phagocytic activity in RAW 264.7 cells. CONCLUSION Pyrrole alkaloids, including a new compound, were isolated from Morus alba fruits. These compounds activated macrophage activity in RAW 264.7 cells.
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Affiliation(s)
- Seon Beom Kim
- College of Pharmacy, Chungbuk National University, Cheongju 361-763, Republic of Korea
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26
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Guirnalda P, Wood L, Paterson Y. Listeria monocytogenes and its products as agents for cancer immunotherapy. Adv Immunol 2012; 113:81-118. [PMID: 22244580 DOI: 10.1016/b978-0-12-394590-7.00004-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
This review covers the use of Listeria monocytogenes and its virulence factors as cancer immunotherapeutics. We describe their development as vectors to carry protein tumor antigen and eukaryotic DNA plasmids to antigen-presenting cells and efforts to harness their tumor-homing properties. We also describe their use as vectors of angiogenic molecules to induce an immune response that will destroy tumor vasculature. The background knowledge necessary to understand the biology behind the rationale to develop Listeria as a vaccine vector for tumor immunotherapy is included as well as a brief summary of the major therapies that have used this approach thus far.
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Affiliation(s)
- Patrick Guirnalda
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Whitworth JM, Alvarez RD. Evaluating the role of IL-12 based therapies in ovarian cancer: a review of the literature. Expert Opin Biol Ther 2011; 11:751-62. [DOI: 10.1517/14712598.2011.566854] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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28
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Pisarska MD, Barlow G, Kuo FT. Minireview: roles of the forkhead transcription factor FOXL2 in granulosa cell biology and pathology. Endocrinology 2011; 152:1199-208. [PMID: 21248146 PMCID: PMC3206711 DOI: 10.1210/en.2010-1041] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The forkhead transcription factor (FOXL2) is an essential transcription factor in the ovary. It is important in ovarian development and a key factor in female sex determination. In addition, FOXL2 plays a significant role in the postnatal ovary and follicle maintenance. The diverse transcriptional activities of FOXL2 are likely attributable to posttranslational modifications and binding to other key proteins involved in granulosa cell function. Mutations of FOXL2 lead to disorders of ovarian function ranging from premature follicle depletion and ovarian failure to unregulated granulosa cell proliferation leading to tumor formation. Thus, FOXL2 is a key regulator of granulosa cell function and a master transcription factor in these cells.
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Affiliation(s)
- Margareta D Pisarska
- Center for Fertility and Reproductive Medicine, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, 8635 West Third Street, Suite 160W, Los Angeles, California 90048, USA.
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29
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RAA NED, RA H, MM E, NA H, MG M. Levels of interleukins 12 (IL-12) and 13 (IL-13), hepatitis B and C serology, and blood cultures among acute myeloid leukemia (AML) patients in Egypt. J Venom Anim Toxins Incl Trop Dis 2011. [DOI: 10.1590/s1678-91992011000300009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
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Enioutina EY, Bareyan D, Daynes RA. A role for immature myeloid cells in immune senescence. THE JOURNAL OF IMMUNOLOGY 2010; 186:697-707. [PMID: 21148798 DOI: 10.4049/jimmunol.1002987] [Citation(s) in RCA: 102] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The reduced efficiency of the mammalian immune system with aging increases host susceptibility to infectious and autoimmune diseases. However, the mechanisms responsible for these pathologic changes are not well understood. In this study, we demonstrate that the bone marrow, blood, and secondary lymphoid organs of healthy aged mice possess increased numbers of immature myeloid cells that are phenotypically similar to myeloid-derived suppressor cells found in lymphoid organs of mice with progressive tumors and other pathologic conditions associated with chronic inflammation. These cells are characterized by the presence of Gr1 and CD11b markers on their surfaces. Gr1(+)CD11b(+) cells isolated from aged mice possess an ability to suppress T cell proliferation/activation and produce heightened levels of proinflammatory cytokines, both constitutively and upon activation, including IL-12, which promotes an excessive production of IFN-γ. IFN-γ priming is essential for excessive proinflammatory cytokine production and the suppressive activities by Gr1(+)CD11b(+) cells from aged mice. These cells suppress T cell proliferation through an NO-dependent mechanism, as depletion of splenic Gr1(+) cells reduces NO levels and restores T cell proliferation. Insights into mechanisms responsible for the proinflammatory and immune suppressive activities of Gr1(+)CD11b(+) cells from aged mice have uncovered a defective PI3K-Akt signaling pathway, leading to a reduced Akt-dependent inactivation of GSK3β. Our data demonstrate that abnormal activities of the Gr1(+)CD11b(+) myeloid cell population from aged mice could play a significant role in the mechanisms responsible for immune senescence.
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Affiliation(s)
- Elena Y Enioutina
- Department of Pathology, University of Utah, Salt Lake City, UT 84132, USA.
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Simone R, Barbarat B, Rabellino A, Icardi G, Bagnasco M, Pesce G, Olive D, Saverino D. Ligation of the BT3 molecules, members of the B7 family, enhance the proinflammatory responses of human monocytes and monocyte-derived dendritic cells. Mol Immunol 2010; 48:109-18. [PMID: 20947169 DOI: 10.1016/j.molimm.2010.09.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2010] [Revised: 09/14/2010] [Accepted: 09/14/2010] [Indexed: 11/26/2022]
Abstract
BT3 is a new family of immunoreceptors belonging to the extended B7 family. BT3 molecules are expressed on the surface of resting and activated monocytes and monocyte-derived dendritic cells (iDC). We show that BT3 cross-linking, in the absence of other survival factors, provides a survival signal for monocytes and iDC and induces up-regulation of costimulatory molecules, such as CD80 and CD86, and HLA-DR. We further analyzed the effects of BT3 cross-linking on various proinflammatory responses on monocytes and iDC. The results obtained showed that BT3 engagement is able to modulate the production of IL8/CXCL8, IL-1β and IL-12/p70. Moreover, we demonstrated a synergistic effect between BT3 and Toll-like receptors ligands on both monocytes and iDC in up-regulating the production of proinflammatory cytokines. Thus, BT3 could be involved in the regulation of the balance between immune activation and suppression. A better understanding of its physiological role of these families of receptors awaits the precise identification of the nature, origin, expression, and distribution of their ligands.
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Affiliation(s)
- Rita Simone
- Department of Experimental Medicine - Section of Human Anatomy, University of Genova, Italy
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Liu L, Xu Y, Liu Z, Chen J, Zhang Y, Zhu J, Liu J, Liu S, Ji G, Shi H, Shen H, Hu Z. IL12 polymorphisms, HBV infection and risk of hepatocellular carcinoma in a high-risk Chinese population. Int J Cancer 2010; 128:1692-6. [PMID: 20521253 DOI: 10.1002/ijc.25488] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2010] [Accepted: 05/27/2010] [Indexed: 12/13/2022]
Abstract
To investigate the association between the potentially functional polymorphisms in IL12A and IL12B, HBV infection and risk of hepatocellular carcinoma in a Chinese population, we genotyped three polymorphisms, rs568408 (3'UTR G>A), rs2243115 (5'UTR T>G) in IL12A and rs3212227 (3'UTR A>C) in IL12B in a case-control study of 869 hepatocellular carcinoma (HCC) cases and 891 cancer-free controls. We found that the IL12A rs568408 GA/AA variant genotypes were associated with a significantly increased risk of HCC (adjusted odds ratio (OR) = 1.53, 95% confidence interval (CI) = 1.17-2.00), compared with the wild-type GG homozygote. In the stratified analyses, the increased risk of HCC associated with rs568408 GA/AA was more evident in patients who were negative for HBsAg (adjusted OR = 1.71, 95% CI = 1.23-2.39). However, no significant associations between IL12A rs2243115 T/G, IL12B rs3212227 A/C and risk of HCC were observed. Our findings indicate that IL12A rs568408 may contribute to the risk of HCC and modify HCC risk associated with HBV infection.
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Affiliation(s)
- Li Liu
- Department of Epidemiology and Biostatistics, Cancer Center, Nanjing Medical University, Nanjing, China
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Hsu CY, Leu SJ, Chiang BL, Liu HE, Su HC, Lee YL. Cytokine gene-modulated dendritic cells protect against allergic airway inflammation by inducing IL-10(+)IFN-gamma(+)CD4(+) T cells. Gene Ther 2010; 17:1011-21. [PMID: 20357831 DOI: 10.1038/gt.2010.39] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Asthma is characterized by allergen-induced airway inflammation orchestrated by Th2 cells. Dendritic cells (DCs) were found to efficiently prime naive T-helper cells. Thus, modification of DC function may be used as an ideal tool to treat allergic asthma by changing CD4(+) T-cell differentiation or suppressing Th2 development. In this study, we examined whether a DC-based vaccine can be applied to DCs modified with interleukin (IL)-10- and IL-12-expressing adenoviruses to prevent ovalbumin (OVA)-induced asthma in mice. Herein, we show that these modified DCs efficiently moderated the characteristics of asthma, including expressions of OVA-specific antibodies, airway hyperresponsiveness, eosinophilic airway inflammation, and Th2 cytokines production. Additionally, IL-10 and IL-12 gene-modified DCs enhanced the development of both T-helper type 1 (Th1) and IL-10(+)IFN-gamma(+) (interferon-gamma) double-positive T cells in vivo. In vitro-generated OVA-specific IL-10(+)IFN-gamma(+)CD4(+) T cells inhibited the proliferation of naive CD4(+) T cells, and this suppressive effect was a cell contact-dependent mechanism. Furthermore, we showed that combined cytokine-modulated DCs could alleviate established allergic airway inflammation. Taken together, these results suggest that IL-10 and IL-12 gene-modulated DCs are effective in suppressing asthmatic airway inflammation through both immune deviation and immune suppression and are a potential therapeutic approach for asthma.
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Affiliation(s)
- C-Y Hsu
- Department of Internal Medicine, Cathay General Hospital, Taipei, Taiwan, ROC
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Hsu CY, Liu HE, Sheu FY, Leu SJ, Chiang BL, Hsiao G, Lee YL. Synergistic therapeutic effects of combined adenovirus-mediated interleukin-10 and interleukin-12 gene therapy on airway inflammation in asthmatic mice. J Gene Med 2010; 12:11-21. [PMID: 19866481 DOI: 10.1002/jgm.1408] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
BACKGROUND Asthma is a chronic disease characterized by airway inflammation caused by the dysregulated production of cytokines secreted by allergen-specific type 2 T helper (Th2) cells. Although the Th1-promoting cytokine, interleukin (IL)-12, is capable of inhibiting Th2-driven allergen-induced airway changes in mice, IL-12 also aggravates the Th1-driven inflammatory pulmonary pathology. Further, IL-10 was found to exert both anti-inflammatory and immunoregulatory activities. To avoid the side-effects of IL-12, we hypothesized that the low-dose expression of IL-10 with concomitant IL-12 administration in the airway may represent a more effective therapy for allergic airway diseases. Thus, the present study explored the immunomodulatory and therapeutic effects of IL-10 combined with IL-12 in airway inflammation in allergic asthma. METHODS Adenovirus-expressing murine IL-10 (Ad-IL-10) and IL-12 (Ad-IL-12) were co-administrated in an established murine model of ovalbumin (OVA)-induced asthma. RESULTS We found that a single combined treatment of low doses of Ad-IL-10 and Ad-IL-12 efficiently inhibited the development of airway hyper-responsiveness compared to Ad-IL-10 or Ad-IL-12 treatment alone. Moreover, both Ad-IL-10 and Ad-IL-12 treatment reduced pulmonary infiltration of eosinophils and neutrophils. In addition, histological studies showed that combined treatment was able to reduce tumor necrosis factor-alpha-mediated airway inflammation induced by IL-12 treatment. Suppression of IL-4, IL-5, Keratinocyte-derived chemokine (KC) and eotaxin in bronchoalveolar lavage fluid was also noted in OVA-immunized mice with combined Ad-IL-10 and Ad-IL-12 treatment. CONCLUSIONS Taken together, the results obtained in the present study indicate that co-administration of IL-12 and IL-10 may have therapeutic potential for the immunomodulatory treatment of allergic asthma.
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Affiliation(s)
- Chih-Yu Hsu
- Department of Internal Medicine, Cathay General Hospital, Taipei, Taiwan, Republic of China
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Wood LM, Pan ZK, Shahabi V, Paterson Y. Listeria-derived ActA is an effective adjuvant for primary and metastatic tumor immunotherapy. Cancer Immunol Immunother 2010; 59:1049-1058. [PMID: 20213121 DOI: 10.1007/s00262-010-0830-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2009] [Accepted: 02/08/2010] [Indexed: 12/25/2022]
Abstract
Tumor immunotherapy is currently at the cusp of becoming an important aspect of comprehensive cancer treatment in the clinic. However, the need for improved adjuvants to augment immune responses against tumor antigens is always present. In this paper, we characterize the Listeria monocytogenes-derived actin-nucleating protein, ActA, as a novel adjuvant for use in tumor immunotherapy. ActA is a virulence factor that is expressed on the cell surface of L. monocytogenes and facilitates the production of actin tails that propel Listeria throughout the cytosol of an infected host cell. It is believed that this ActA-dependent cytosolic motility allows Listeria to evade adaptive host cell defenses and facilitates its invasion into a proximal uninfected host cell. However, there is evidence that ActA fused to a tumor antigen and delivered by L. monocytogenes can perform a beneficial function in tumor immunotherapy as an adjuvant. Our investigation of this adjuvant activity demonstrates that ActA, either fused to or administered as a mixture with a tumor antigen, can augment anti-tumor immune responses, break immune tolerance and facilitate tumor eradication, which suggests that ActA is not only an effective adjuvant in tumor immunotherapy but can also be applied in a number of therapeutic settings.
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Affiliation(s)
- Laurence M Wood
- University of Pennsylvania, Department of Microbiology, 323 Johnson Pavilion, Philadelphia, PA 19104
| | - Zhen-Kun Pan
- University of Pennsylvania, Department of Microbiology, 323 Johnson Pavilion, Philadelphia, PA 19104
| | - Vafa Shahabi
- Advaxis Inc., The Technology Centre of New Jersey, Suite 117, 675 U.S. Route 1, North Brunswick, NJ 08902
| | - Yvonne Paterson
- University of Pennsylvania, Department of Microbiology, 323 Johnson Pavilion, Philadelphia, PA 19104
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Apostolakis S, Lip GYH, Shantsila E. Monocytes in heart failure: relationship to a deteriorating immune overreaction or a desperate attempt for tissue repair? Cardiovasc Res 2009; 85:649-60. [PMID: 19805399 DOI: 10.1093/cvr/cvp327] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Monocytes play an important role in immune defence, inflammation, and tissue remodelling. Nevertheless, the role of monocytes in cardiovascular disease is obscure. Indeed, monocytes infiltrate dysfunctional tissue and augment tissue damage and are actively involved in tissue regeneration and healing. In support of the latter, recent studies have provided data on the functional and structural plasticity of monocytes. Monocytes are also actively involved in processes associated with tissue regeneration such as angiogenesis and vasculogenesis, either by producing pro-angiogenic factors or even by evolving to structural components of the vascular wall. This review article provides an overview on whether monocytes represent deteriorating immune overreaction in heart failure (HF), or a desperate attempt for tissue repair or physiological compensation in the failing heart. Perhaps, it is time to reconsider our attitude towards monocytes and consider more 'monocyte activation' rather than 'monocyte suppression' as a potential therapeutic target in HF.
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Affiliation(s)
- Stavros Apostolakis
- Haemostasis Thrombosis and Vascular Biology Unit, University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham B18 7QH, UK
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Gómez-Laguna J, Salguero FJ, De Marco MF, Pallarés FJ, Bernabé A, Carrasco L. Changes in lymphocyte subsets and cytokines during European porcine reproductive and respiratory syndrome: increased expression of IL-12 and IL-10 and proliferation of CD4(-)CD8(high). Viral Immunol 2009; 22:261-71. [PMID: 19594397 DOI: 10.1089/vim.2009.0003] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
The changes in peripheral blood mononuclear cells (PBMCs) have been studied in several reports in an attempt to determine the immune response against porcine reproductive and respiratory syndrome virus (PRRSV) infection. However, how these changes are evoked after PRRSV infection has not yet been clarified. The aim of this study was to analyze the changes seen in lymphocyte subsets and immunomodulatory cytokine expression in pigs after an acute experimental infection with a European PRRSV field isolate. Pigs were inoculated intramuscularly with PRRSV field isolate 2982. Samples from blood, medial retropharyngeal and tracheobronchial lymph nodes, and spleen were collected at different time points for flow cytometry studies and for cytokine expression by ELISA. CD21(+) cell counts increased in PBMCs and tracheobronchial lymph node cells from 17 to 24 dpi, coinciding with an increase in PRRSV-specific antibody titer in blood. CD3(+) T-cell counts increased mainly due to an enhancement of CD4(-)CD8(high) and CD4(+)CD8(+) T cells. CD4(-)CD8(low) T cells were decreased in all organs studied, whereas CD4(+)CD8(-) T cells decreased only in the spleen. The drop in viremia correlated with an enhancement of CD4(-)CD8(high) T cells, and with a higher expression of interleukin-10 (IL-10) and interleukin-12 p40 (IL-12 p40). No efficient interferon-gamma (IFN-gamma) response was detected during the acute phase of the infection, and the expression of interferon-alpha (IFN-alpha) was late and reached its maximum expression once the viremia decreased. These results point to IL-10 and IL-12 as cytokines that might play a significant role in the PRRSV immune response, as may CD4(-)CD8(high) T cells.
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Affiliation(s)
- Jaime Gómez-Laguna
- Department of Anatomy and Comparative Pathology, Faculty of Veterinary Medicine, Córdoba University, Campus de Rabanales, Edificio de Sanidad Animal, Córdoba, Spain.
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Jung ID, Lee MG, Chang JH, Lee JS, Jeong YI, Lee CM, Park WS, Han J, Seo SK, Lee SY, Park YM. Blockade of Indoleamine 2,3-Dioxygenase Protects Mice against Lipopolysaccharide-Induced Endotoxin Shock. THE JOURNAL OF IMMUNOLOGY 2009; 182:3146-54. [DOI: 10.4049/jimmunol.0803104] [Citation(s) in RCA: 88] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Cutaneous Hypersensitivities to Hapten Are Controlled by IFN-γ-Upregulated Keratinocyte Th1 Chemokines and IFN-γ-Downregulated Langerhans Cell Th2 Chemokines. J Invest Dermatol 2008; 128:1719-27. [DOI: 10.1038/jid.2008.5] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Wang H, Chen S. Immune killing activity of lymphocytes on Hela cells expressing interleukin-12 in vitro. ACTA ACUST UNITED AC 2008; 28:343-5. [PMID: 18563338 DOI: 10.1007/s11596-008-0326-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2008] [Indexed: 11/27/2022]
Abstract
The killing effects of lymphocytes on Hela cells expressing interleukin-12 (IL-12) in vitro were explored. By using gene transfection technique, full length IL-12 gene was transfected into Hela cells. The expression of IL-12 in Hela cells was detected quantitatively by ELISA; Changes in killing effects of lymphocytes on Hela cells expressing IL-12 were observed by MTT. It was found that Hela cells could express IL-12 between 24 h and 72 h after transfection. Killing activity of lymphocytes on Hela cells expressing IL-12 was significantly enhanced. It was concluded by cell transfection technique, Hela cells could express IL-12 and were more easily killed by lymphocytes.
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Affiliation(s)
- Huiyan Wang
- Hospital of Wuhan University of Technology, Wuhan 430070, China.
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D'Aiuto L, Robison CS, Gigante M, Nwanegbo E, Shaffer B, Sukhwani M, Castro CA, Chaillet JR. Human IL-12 p40 as a reporter gene for high-throughput screening of engineered mouse embryonic stem cells. BMC Biotechnol 2008; 8:52. [PMID: 18522747 PMCID: PMC2442052 DOI: 10.1186/1472-6750-8-52] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2008] [Accepted: 06/03/2008] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Establishing a suitable level of exogenous gene expression in mammalian cells in general, and embryonic stem (ES) cells in particular, is an important aspect of understanding pathways of cell differentiation, signal transduction and cell physiology. Despite its importance, this process remains challenging because of the poor correlation between the presence of introduced exogenous DNA and its transcription. Consequently, many transfected cells must be screened to identify those with an appropriate level of expression. To improve the screening process, we investigated the utility of the human interleukin 12 (IL-12) p40 cDNA as a reporter gene for studies of mammalian gene expression and for high-throughput screening of engineered mouse embryonic stem cells. RESULTS A series of expression plasmids were used to study the utility of IL-12 p40 as an accurate reporter of gene activity. These studies included a characterization of the IL-12 p40 expression system in terms of: (i) a time course of IL-12 p40 accumulation in the medium of transfected cells; (ii) the dose-response relationship between the input DNA and IL-12 p40 mRNA levels and IL-12 p40 protein secretion; (iii) the utility of IL-12 p40 as a reporter gene for analyzing the activity of cis-acting genetic elements; (iv) expression of the IL-12 p40 reporter protein driven by an IRES element in a bicistronic mRNA; (v) utility of IL-12 p40 as a reporter gene in a high-throughput screening strategy to identify successful transformed mouse embryonic stem cells; (vi) demonstration of pluripotency of IL-12 p40 expressing ES cells in vitro and in vivo; and (vii) germline transmission of the IL-12 p40 reporter gene. CONCLUSION IL-12 p40 showed several advantages as a reporter gene in terms of sensitivity and ease of the detection procedure. The IL-12 p40 assay was rapid and simple, in as much as the reporter protein secreted from the transfected cells was accurately measured by ELISA using a small aliquot of the culture medium. Remarkably, expression of Il-12 p40 does not affect the pluripotency of mouse ES cells. To our knowledge, human IL-12 p40 is the first secreted reporter protein suitable for high-throughput screening of mouse ES cells. In comparison to other secreted reporters, such as the widely used alkaline phosphatase (SEAP) reporter, the IL-12 p40 reporter system offers other real advantages.
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Affiliation(s)
- Leonardo D'Aiuto
- Department of Cell Biology and Physiology, Pittsburgh Development Center, Magee-Women's Research Institute, University of Pittsburgh School of Medicine, PA 15261, USA.
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Park EK, Bae SM, Kwak SY, Lee SJ, Kim YW, Han CH, Cho HJ, Kim KT, Kim YJ, Kim HJ, Ahn WS. Photodynamic therapy with recombinant adenovirus AdmIL-12 enhances anti-tumour therapy efficacy in human papillomavirus 16 (E6/E7) infected tumour model. Immunology 2008; 124:461-8. [PMID: 18397271 DOI: 10.1111/j.1365-2567.2007.02797.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Immunotherapy with photodynamic therapy (PDT) offers great promise as a new alternative for cancer treatment; however, its use remains experimental. Here we investigated the utility of adenoviral delivery of interleukin-12 (AdmIL-12) as an adjuvant for PDT in mouse tumour challenge model. PDT was performed by irradiating Radachlorin in C57BL/6 mice transplanted with TC-1 cells. PDT plus AdmIL-12 treatment for tumour suppression as well as specific immune responses were evaluated with the following tests: in vitro and in vivo tumour growth inhibition, interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) assay, and cytotoxic T lymphocyte (CTL) assay. Direct intratumoral injection of AdmIL-12 resulted in a significant suppression of tumour growth compared to the control group. Treatment of PDT along with AdmIL-12 further enhanced antitumour effects significantly higher than either AdmIL-12 or PDT alone. This combined treatment resulted in complete regression of 9-mm sized tumour in every animal. We also evaluated immune responses induced by these treatments. Combined treatment significantly increased the production level of IFN-gamma and TNF-alpha compared with that by AdmIL-12 or PDT alone. PDT plus AdmIL-12 enhanced antitumour immunity through increased expansion of the CTL subset mediated by CD8+ T cells. Taken together, these results indicate that the high anti-cancer activity of PDT with AdmIL-12 is a powerful tool against cancer therapy and is a promising subject for further investigation.
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Affiliation(s)
- Eun Kyung Park
- Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, Seoul, Korea
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Lee YS, Kim JH, Choi KJ, Choi IK, Kim H, Cho S, Cho BC, Yun CO. Enhanced antitumor effect of oncolytic adenovirus expressing interleukin-12 and B7-1 in an immunocompetent murine model. Clin Cancer Res 2006; 12:5859-68. [PMID: 17020994 DOI: 10.1158/1078-0432.ccr-06-0935] [Citation(s) in RCA: 103] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE We investigated whether an armed viral platform, where lytic property of a viral infection is coupled to viral-mediated delivery of therapeutic genes, could increase the therapeutic potential of a viral-based therapy. EXPERIMENTAL DESIGN We generated interleukin (IL)-12-expressing oncolytic adenovirus (YKL-IL-12) and IL-12- and B7-1-expressing (YKL-IL12/B7) oncolytic adenovirus. Therapeutic efficacy of these newly engineered adenoviruses was then evaluated in vivo using an immunocompetent mouse bearing murine melanoma B16-F10 tumors. Overall survival was assessed with the Kaplan-Meier method. The induction of immune cell cytotoxicity was assessed by CTL assay, IFN-gamma enzyme-linked immunospot assay, and immunohistochemical studies. RESULTS YKL-IL12/B7 oncolytic adenovirus, expressing both IL-12 and B7-1, showed a higher incidence of complete tumor regression compared with the analogous oncolytic adenovirus, YKL-1, or IL-12-expressing, YKL-IL12. Significant survival advantage was also seen in response to YKL-IL12/B7. Moreover, IL-12 and IFN-gamma levels produced in tumors treated with YKL-IL12/B7 was significantly greater than those treated with YKL-IL12. The enhanced survival advantage was mediated by the induction of immune cell cytotoxicity. In agreement with these results, massive infiltration of CD4(+) and CD8(+) T cells into tissues surrounding the necrotic area of the tumor was observed following in situ delivery of YKL-IL12/B7. CONCLUSION Combination of oncolysis and the enhancement of antitumor immune response by oncolytic adenovirus expressing both IL-12 and B7-1 elicits potent antitumor effect and survival advantage.
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Affiliation(s)
- Young-Sook Lee
- Brain Korea 21 Project for Medical Science, Institute for Cancer Research, Yonsei Cancer Center, Yonsei University College of Medicine, 134 Shinchon-Dong, Seodaemun-Gu, Seoul 120-752, Korea
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Stevens DA, Brummer E, Clemons KV. Interferon- gamma as an antifungal. J Infect Dis 2006; 194 Suppl 1:S33-7. [PMID: 16921470 DOI: 10.1086/505357] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Affiliation(s)
- David A Stevens
- Department of Medicine, Santa Clara Valley Medical Center and California Institute for Medical Research, San Jose, CA, 95128, USA.
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45
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Hu ZQ, Zhao WH, Shimamura T. Mechanisms of strain-dependent development of mast cells from mouse splenocytes. Immunol Cell Biol 2006; 84:184-91. [PMID: 16519736 DOI: 10.1111/j.1440-1711.2005.01410.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Mast cell development from spleen cells was not triggered by prostaglandin E1 (PGE1) or dibutyryl cAMP (db-cAMP) during a 12 day culture when the spleen cells were obtained from C57BL/6N and DBA/1 mice, but mast cells did develop when the spleen cells were obtained from C3H/HeN, BALB/c and ICR mice. A lack of endogenous IFN-gamma in the initial 2 days of the culture period was responsible for the failure. This was confirmed by adding neutralizing anti-IFN-gamma antibody and rIFN-gamma to the cultures and by determining IFN-gamma levels in the spleen cell cultures. Th1 cells in the spleens of C57Bl and DBA/1 mice were much more sensitive to PGE1 and db-cAMP than Th1 cells from other inbred mice strains, and consequently, IFN-gamma production was inhibited in spleen cell cultures of C57BL and DBA/1 mice on addition of PGE1 or db-cAMP. Furthermore, the different sensitivities of Th1 cells to PGE and db-cAMP were dependent on the different levels of IL-12 p40 monomers or homodimers in the spleen cell cultures. As the endogenous specific inhibitors of IL-12 p70 (heterodimers of p40 and p35), large amounts of IL-12 p40 monomers or homodimers in the spleen cell cultures of C57BL and DBA/1 mice enhanced the ability of PGE1 and db-cAMP to inhibit IFN-gamma production by antagonizing the activity of IL-12 heterodimers. These results indicate that the strain-dependent development of mast cells from mouse splenocytes is related to endogenous IFN-gamma levels, which are regulated by PGE, db-cAMP, IL-12 p70 and IL-12 p40.
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Affiliation(s)
- Zhi-Qing Hu
- Department of Microbiology and Immunology, Showa Univrsity School of Medicine, Tokyo, Japan.
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Trudeau C, Cotreau MM, Stonis L, Dykstra KH, Oestreicher JL, Strahs A, Dorner AJ, Van Cleave VH, Trepicchio WL, Schwertschlag US. A single administration of recombinant human interleukin-12 is associated with increased expression levels of interferon-gamma and signal transducer and activator of transcription in healthy subjects. J Clin Pharmacol 2006; 45:649-58. [PMID: 15901746 DOI: 10.1177/0091270005276116] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The objectives of this study were to assess the safety and tolerability of single doses of 1, 4, and 8 mug of recombinant human interleukin-12 (rhIL-12) administered subcutaneously to healthy subjects. The pharmacokinetics, pharmacodynamics, and pharmacogenomics of rhIL-12 were evaluated. Recombinant human IL-12 was well tolerated in these healthy male and female subjects. The most frequently reported adverse events were flu-like symptoms, which exhibited a dose-response relationship. Pharmacokinetic analysis suggested that serum IL-12 levels increased with dose. Analysis of serum levels indicated that interferon-gamma increased with the dose of rhIL-12, whereas IL-6 levels showed no changes with rhIL-12 treatment. The messenger ribonucleic acid expression of signal transducer and activator of transcription was significantly increased 24 hours after the administration of rhIL-12 for all dose groups versus placebo, and results indicated that the magnitude of increase may be dose dependent. This study suggests that interferon-gamma and signal transducer and activator of transcription are biomarkers of rhIL-12 activity.
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Affiliation(s)
- Caroline Trudeau
- Experimental Medicine, Wyeth Research, 35 Cambridge Park Drive, Cambridge, MA 02140, USA
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Ireland DD, Palian BM, Reiss CS. Interleukin (IL)-12 receptor beta1 or IL-12 receptor beta 2 deficiency in mice indicates that IL-12 and IL-23 are not essential for host recovery from viral encephalitis. Viral Immunol 2005; 18:397-402. [PMID: 16035952 PMCID: PMC1237019 DOI: 10.1089/vim.2005.18.397] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Vesicular stomatitis virus (VSV), a negative-sense, single-stranded RNA rhabdovirus, causes acute viral encephalitis when administered intranasally to mice. Interleukin-12 (IL-12) is a key pro-inflammatory cytokine that is produced largely by the antigen presenting cells (APC) and that bridges the innate and acquired immune responses. IL-12 is efficacious in enhancing recovery from VSV infection of the murine central nervous system. This effect is mediated by nitric oxide (NO) produced by the neuronal isoform of nitric oxide synthase (NOS-1), and is independent of the pro-inflammatory cytokines interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). These data implied a link between IL-12 and NOS-1. Here we investigate the role of the IL-12R during VSV pathogenesis, using IL-12R beta2 and IL-12R beta1-deficient mice. We showed that a deficiency in either IL-12R beta2 or IL-12R beta1 had no effect on the outcome of VSV infection of the CNS or on the clearance of VSV from the CNS. Furthermore, these data indicate that IL-23 is not acting redundantly in the absence of IL-12 during VSV-induced encephalitis.
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Affiliation(s)
- Derek D.C. Ireland
- Department of Neurology, Keck School of Medicine, University of Southern California, 1333 San Pablo St., Mail Code 9153, Los Angeles, CA 91030
| | - Beth M. Palian
- Department of Neurology, Keck School of Medicine, University of Southern California, 1333 San Pablo St., Mail Code 9153, Los Angeles, CA 91030
| | - Carol Shoshkes Reiss
- Department of Biology
- Center for Neural Science
- Department of Microbiology and
- Kaplan Comprehensive Cancer Center, New York University
- Department of Microbiology, Mt. Sinai School of Medicine 100 Washington Square East, mail code 5181 New York, NY 10003-6688
- Corresponding author: Carol Shoshkes Reiss,
, Phone: 212-998-8243, Fax: 212-995-4015
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Hwang KS, Cho WK, Yoo J, Yun HJ, Kim S, Im DS. Adenovirus-mediated interleukin-12 gene transfer combined with cytosine deaminase followed by 5-fluorocytosine treatment exerts potent antitumor activity in Renca tumor-bearing mice. BMC Cancer 2005; 5:51. [PMID: 15910693 PMCID: PMC1168891 DOI: 10.1186/1471-2407-5-51] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2004] [Accepted: 05/24/2005] [Indexed: 12/04/2022] Open
Abstract
BACKGROUND Therapeutic gene transfer affords a clinically feasible and safe approach to cancer treatment but a more effective modality is needed to improve clinical outcomes. Combined transfer of therapeutic genes with different modes of actions may be a means to this end. Interleukin-12 (IL-12), a heterodimeric immunoregulatory cytokine composed of covalently linked p35 and p40 subunits, has antitumor activity in animal models. The enzyme/prodrug strategy using cytosine deaminase (CD) and 5-fluorocytosine (5-FC) has been used for cancer gene therapy. We have evaluated the antitumor effect of combining IL-12 with CD gene transfer in mice bearing renal cell carcinoma (Renca) tumors. METHODS Adenoviral vectors were constructed encoding one or both subunits of murine IL-12 (Ad.p35, Ad.p40 and Ad.IL-12) or cytosine deaminase (Ad.CD). The functionality of the IL-12 or CD gene products expressed from these vectors was validated by splenic interferon (IFN)-gamma production or viability assays in cultured cells. Ad.p35 plus Ad.p40, or Ad.IL-12, with or without Ad.CD, were administered (single-dose) intratumorally to Renca tumor-bearing mice. The animals injected with Ad.CD also received 5-FC intraperitoneally. The antitumor effects were then evaluated by measuring tumor regression, mean animal survival time, splenic natural killer (NK) cell activity and IFN-gamma production. RESULTS The inhibition of tumor growth in mice treated with Ad.p35 plus Ad.p40 and Ad.CD, followed by injection of 5-FC, was significantly greater than that in mice treated with Ad.CD/5-FC, a mixture of Ad.p35 plus Ad.p40, or Ad.GFP (control). The combined gene transfer increased splenic NK cell activity and IFN-gamma production by splenocytes. Ad.CD/5-FC treatment significantly increased the antitumor effect of Ad.IL-12 in terms of tumor growth inhibition and mean animal survival time. CONCLUSION The results suggest that adenovirus-mediated IL-12 gene transfer combined with Ad.CD followed by 5-FC treatment may be useful for treating cancers.
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Affiliation(s)
- Kyung-Sun Hwang
- Laboratory of Gene Therapy and Virology, Korea Research Institute of Bioscience and Biotechnology, Yusong, Daejeon, Republic of Korea
| | - Won-Kyung Cho
- Laboratory of Gene Therapy and Virology, Korea Research Institute of Bioscience and Biotechnology, Yusong, Daejeon, Republic of Korea
| | - Jinsang Yoo
- Laboratory of Gene Therapy and Virology, Korea Research Institute of Bioscience and Biotechnology, Yusong, Daejeon, Republic of Korea
| | - Hwan-Jung Yun
- Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Samyong Kim
- Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Dong-Soo Im
- Laboratory of Gene Therapy and Virology, Korea Research Institute of Bioscience and Biotechnology, Yusong, Daejeon, Republic of Korea
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Janát-Amsbury MM, Yockman JW, Lee M, Kern S, Furgeson DY, Bikram M, Kim SW. Local, non-viral IL-12 gene therapy using a water soluble lipopolymer as carrier system combined with systemic paclitaxel for cancer treatment. J Control Release 2005; 101:273-85. [PMID: 15588911 DOI: 10.1016/j.jconrel.2004.08.015] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2004] [Accepted: 08/26/2004] [Indexed: 11/27/2022]
Abstract
Development of improved gene transfer methods is needed for gene therapy to achieve its clinical potential. The use of biocompatible polymeric gene carriers has shown effectiveness in overcoming the current problems associated with viral vectors in safety, immunogenicity and mutagenesis. Previous work has demonstrated that repeated, local, non-viral interleukin-12 (IL-12) gene delivery successfully slows down tumor progression, while improving immunogenicity. Combining IL-12 gene delivery with systemic paclitaxel (PCT) chemotherapy as a treatment for various subcutaneous mouse mammary carcinomas, we used PCT with either a biodegradable polymeric solubilizer, HySolv or Cremophor EL for systemic treatment and injected water soluble lipopolymer (WSLP)/plasmid-encoding IL-12 gene (p2CMVmIL-12) complexes local once every week. The amount of lung metastases being essential for survival as well as subcutaneous tumor volume were compared against untreated controls. We showed inhibition of tumor growth and decreased lung metastases in the combined WSLP/p2CMVmIL-12/HySolv group compared to the controls and the PCT only treated groups. Compared to Cremophor, HySolv performed better alone or in combination with IL-12. Using polymeric vectors as gene carrier systems in combination with improved systemic therapies provide evidence for the efficacy and feasibility of polymer-based drug delivery systems. Especially local cytokine gene delivery showed augmentation of systemic chemotherapy while reducing the hosts risk for further systemic toxicity.
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Affiliation(s)
- Margit Maria Janát-Amsbury
- Center for Controlled Chemical Delivery, Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA
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García-González MA, Lanas A, Wu J, Benito R, Santolaria S, Crusius B, Peña S. Lack of association of IL-12 p40 gene polymorphism with peptic ulcer disease. Hum Immunol 2005; 66:72-6. [PMID: 15620465 DOI: 10.1016/j.humimm.2004.10.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Interleukin 12 (IL-12) is a proinflammatory cytokine composed by two chains, p40 and p35, that plays a key role in the promotion of a Th1 immune response in the gastrointestinal mucosa. An enhanced expression of IL-12 mRNA in gastric mucosa has been reported in individuals infected by Helicobacter pylori. The aim of our study was to assess whether a functional polymorphism located at position 1188 (A-->C) of the IL-12 p40 (IL12B) gene is associated with the susceptibility and clinical features of peptic ulcer disease. Genotyping of 184 unrelated white Spanish patients with peptic ulcer and 107 healthy controls was performed by polymerase chain reaction and restriction fragment length polymorphism. Helicobacter pylori status and nonsteroidal antiinflammatory drugs use were studied in patients and controls. There were no significant differences in carriage, genotype, and allele frequencies of the IL-12 p40 gene polymorphism between patients with peptic ulcer and controls. Moreover, no differences were found with respect to the localization of the ulcer, Helicobacter pylori status, nonsteroidal antiinflammatory drug use, age, sex, bleeding episodes, and family history of peptic ulcer. Our data reveal that the IL12B 1188 (A-->C) gene polymorphism is not involved in defining the genetic basis of the susceptibility to and final outcome of peptic ulcer disease.
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Affiliation(s)
- María A García-González
- Instituto Aragonés de Ciencias de la Salud & Department of Gastroenterology, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain.
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