• Autoimmune diseases
• Cytokine
• IL-12
• IL-23
• IL-35

• IL-12
• IL-12R
• IL-12p40(2)
• IL-2
• IL-23
• Microglia
• Neuroinflammation

• Humans
• Animals
• Mice
• Interleukin-12/metabolism
• Microglia/metabolism
• Multiple Sclerosis
• Interleukin-2/metabolism
• Macrophages/metabolism
• Encephalomyelitis, Autoimmune, Experimental
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Interleukin-23

• I01 BX005613 BLRD VA
• IK6 BX004982 BLRD VA
• R01 AT010980 NCCIH NIH HHS
• R01 AG050431 NIA NIH HHS
• I01 BX005002 BLRD VA

• Disease pathogenesis
• Graves' orbitopathy
• Interleukin-23 receptor
• Leptin receptor
• Orbital fibroblast activating factors
• Plasminogen activator inhibitor-1

• colorectal cancer
• cytokine
• inflammation
• tumor microenvironment

• Animals
• Colorectal Neoplasms/immunology
• Humans
• Immune System/immunology
• Inflammation/immunology
• Interleukins/immunology
• Tumor Microenvironment/immunology

• Autoimmune Diseases/immunology
• Cytokines/physiology
• Disease
• Humans
• Inflammation/immunology
• STAT4 Transcription Factor/metabolism
• STAT4 Transcription Factor/physiology
• Signal Transduction

• C-reactive protein- carcinoembryonic antigen
• Colorectal cancer- interleukin-23

Macrophages play an important role in the host immune response to Mycobacterium avium subsp. paratuberculosis (MAP) infection, however, MAP is able to disrupt normal macrophage functions to avoid destruction. It is unclear whether the phenotypes of macrophages present in the target tissue play a role in the inability to clear MAP infection. The aim of this study was to identify macrophage phenotypes (host defense or resolution and repair) present within the bovine ileum of naturally infected cattle, as well as to ascertain abundance of each macrophage phenotype present during different stages of MAP infection. Immunofluorescent (IF) labeling was performed on frozen bovine mid-ileal tissue sections collected from 28 Holstein dairy cows. Comprehensive IF staining for cytokines, such as IFN-γ, IL-1Ra, IL-1β, IL-10, TGF-β, TNF-α, and uNOS, along with markers such as CD163, CD206, and TLR4, served to define the macrophage phenotypes. Overall, cows in the clinical stage of disease demonstrated significantly higher numbers of resolution and repair macrophages and lower numbers of host defense macrophages in the ileal tissue. Interestingly, subclinically affected cows with asymptomatic disease had a nearly equal ratio of host defense and resolution and repair macrophage phenotypes, whereas macrophage phenotype was skewed to a host defense macrophage in the tissues of the control noninfected cows. The preponderance of M2-like resolution and repair phenotype for macrophages in the tissues of cows with clinical disease would explain why the host fails to control and/or clear the infection, leading to a higher MAP burden. The results of the current study offer insight into the disparate macrophage phenotypes present in the bovine ileum during different stages of infection.

• Animals
• Antigens, CD/genetics
• Antigens, Differentiation, Myelomonocytic/genetics
• Cattle
• Cattle Diseases/genetics
• Cattle Diseases/microbiology
• Cattle Diseases/physiopathology
• Cytokines/genetics
• Intestines/microbiology
• Intestines/pathology
• Lectins, C-Type/genetics
• Macrophages/microbiology
• Macrophages/pathology
• Mannose Receptor
• Mannose-Binding Lectins/genetics
• Mycobacterium avium subsp. paratuberculosis/genetics
• Mycobacterium avium subsp. paratuberculosis/pathogenicity
• Paratuberculosis/microbiology
• Paratuberculosis/pathology
• Receptors, Cell Surface/genetics
• Toll-Like Receptor 4/genetics

• Cigarette smoke
• House dust mite
• IL-23
• IL-23 receptor

Mesenchymal stem cells derived from the chorionic villi of human placentae (pMSCs) produce a unique array of mediators that regulate the essential cellular functions of their target cells. These properties make pMSCs attractive candidates for cell-based therapy. Here, we examined the effects of culturing human natural killer (NK) cells with pMSCs on NK cell functions.

pMSCs were cultured with IL-2-activated and non-activated NK cells. NK cell proliferation and cytolytic activities were monitored. NK cell expression of receptors mediating their cytolytic activity against pMSCs, and the mechanisms underlying this effect on pMSCs, were also investigated.

Our findings show that IL-2-activated NK cells, but not freshly isolated NK cells, efficiently lyse pMSCs and that this response might involve the activating NK cell receptor CD69. Interestingly, although pMSCs expressed HLA class I molecules, they were nevertheless lysed by NK cells, suggesting that HLA class I antigens do not play a significant role in protecting pMSCs from NK cell cytolytic activity. Co-culturing NK cells with pMSCs also inhibited NK cell expression of receptors, including CD69, NKpG2D, CD94, and NKp30, although these co-cultured NK cells were not inhibited in lysing cancer cells in vitro. Importantly, co-cultured NK cells significantly increased their production of molecules with anti-tumor effects.

These findings suggest that pMSCs might have potential applications in cancer therapy.

• Cancer
• Chorionic villous mesenchymal stem/multipotent stromal cells
• Cytolytic activity
• Inflammatory molecules
• NK cell proliferation
• NK cells

• Animals
• Diphtheria Toxin/administration & dosage
• Diphtheria Toxin/pharmacology
• Disease Models, Animal
• Humans
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Paracoccidioides/immunology
• Paracoccidioides/pathogenicity
• Paracoccidioidomycosis/immunology
• T-Lymphocytes, Regulatory/drug effects
• T-Lymphocytes, Regulatory/immunology
• Th1 Cells/immunology
• Th17 Cells/immunology

• National Research Council, CNPq, Brazil
• Foundation for Research Support of the State of São Paulo, FAPESP
• Foundation for Research Support of the State of Sao Paulo, FAPESP
• Foundation for Research Support of the State of São Paulo, FAPESP National Research Council, CNPq, Brazil Nacional Research Council Cnpq Brazil

• 7G10
• Interleukin 23
• antigen-antibody docking
• binding free energy
• computer-aided antibody design
• interaction energy

Germline missense mutations in GJB2 encoding connexin (Cx) 26 have been found in keratitis, ichthyosis and deafness (KID) syndrome. We explored the effects of three mouse Cx26 mutants (Cx26-G12R, -G45E and -D50N) corresponding to KID syndrome-causative human mutants on hemichannel activities leading to cell death and the expression of immune response-associated genes. We analyzed the 3D images of cells expressing wild-type (WT) or mutant Cx26 molecules to demonstrate clearly the intracellular localization of Cx26 mutants and hemichannel formation. High extracellular Ca²⁺ conditions lead to the closure of gap junction hemichannels in Cx26-G12R or Cx26-G45E expressing cells, resulting in prohibition of the Cx26 mutant-induced cell death. Fluorescent dye uptake assays revealed that cells with Cx26-D50N had aberrantly high hemichannel activities, which were abolished by a hemichannel blocker, carbenoxolone and 18α-Glycyrrhetinic acid. These results further support the idea that abnormal hemichannel activities play important roles in the pathogenesis of KID syndrome. Furthermore, we revealed that the expressions of IL15, CCL5, IL1A, IL23R and TLR5 are down-regulated in keratinocytes expressing Cx26-D50N, suggesting that immune deficiency in KID syndrome expressing Cx26-D50N might be associated not only with skin barrier defects, but also with the down-regulated expression of immune response-related genes.

• cancer
• janus tyrosine kinases (JAKs)
• proliferation
• signal transducers and activators of transcription (STATs)
• signaling pathways
• survival

Interleukin (IL)-23 is a member of the IL-12 family of cytokines that, as the other members of this family, is secreted by monocytes, macrophages, and dendritic cells (DC) upon recognition of bacterial, viral, and fungal components. IL-23 is critical during immunity against acute infections, and it is also involved in the development of autoimmune diseases. Although immunoregulatory effects of IL-23 on mouse natural killer (NK) cells have been described, the effect of IL-23 on human NK cells remains ill-defined. In this study, we observed that monocytes stimulated with LPS secreted IL-23 and that blockade of this cytokine during monocyte and NK cell coculture led to a diminished production of IFN-γ by NK cells. Accordingly, rIL-23-induced NK cell activation and stimulated IFN-γ production by CD56^bright NK cells. This effect involved MEK1/MEK2, JNK, PI3K, mammalian target of rapamycin, and NF-κB, but not STAT-1, STAT-3, nor p38 MAPK pathways. Moreover, while NK cell-mediated cytotoxicity remained unaltered, antibody-dependent cellular cytotoxicity (ADCC) was enhanced after IL-23 stimulation. In addition, IL-23 displayed a synergistic effect with IL-18 for IFN-γ production by both CD56^bright and CD56^dim NK cells, and this effect was due to a priming effect of IL-23 for IL-18 responsiveness. Furthermore, NK cells pre-stimulated with IL-18 promoted an increase in CD86 expression and IL-12 secretion by DC treated with LPS, and IL-23 potentiated these effects. Moreover, IL-23-driven enhancement of NK cell “helper” function was dependent on NK cell-derived IFN-γ. Therefore, our results suggest that IL-23 may trigger NK cell-mediated “helper” effects on adaptive immunity, shaping T cell responses during different pathological situations through the regulation of DC maturation.

• IFN-γ
• dendritic cells
• interleukin-18
• interleukin-23
• natural killer cells

• Hepatocellular carcinoma
• IL-23R rs7517847 and LEP rs7799039
• genetic polymorphisms

• Carcinoma, Hepatocellular/genetics
• Case-Control Studies
• Egypt
• Female
• Genotype
• Humans
• Leptin/genetics
• Liver Neoplasms/genetics
• Male
• Middle Aged
• Polymorphism, Single Nucleotide
• Receptors, Interleukin/genetics

• Autoimmunity
• Cytokines
• Immunology
• Multiple sclerosis
• T cells

IL-23, which is composed of p19 and p40 subunits, is a proinflammatory cytokine that contributes to the formation and maintenance of Th17 cells in inflammatory autoimmune diseases. IL-23 is a human osteoclastogenic cytokine and anti-IL-23 antibody attenuates paw volume and joint destruction in CIA rats. IL-23 levels in serum and synovial fluid are high in rheumatoid arthritis (RA) patients, and IL-23 may be a useful biomarker for the diagnosis of RA. In addition, IL-23 affects the pathogenesis of inflammation and bone destruction through interaction with other cytokines such as IL-17 and TNF-α. Furthermore, polymorphisms of IL23R are a risk factor for ankylosing spondylitis (AS) and psoriatic arthritis (PsA), which indicates that IL-23 is also involved in the pathogenesis of spondyloarthritis (SpA). Finally, IL-17 and IL-23 inhibitors reduce the clinical manifestations of SpA. Thus, the IL-23/Th17 pathway is a therapeutic target for the treatment of inflammatory arthritis.

• IL-23
• ankylosing spondylitis
• psoriatic arthritis
• rheumatoid arthritis
• spondyloarthritis

Tuberculosis (TB) is an airborne infection caused by Mycobacterium tuberculosis (Mtb). About one-third of the world's population is latently infected with TB and 5–15% of them will develop active TB in their lifetime. It is estimated that each case of active TB may cause 10–20 new infections. Host immune response to Mtb is influenced by interferon- (IFN-) signaling pathways, particularly by type I and type II interferons (IFNs). The latter that consists of IFN-γ has been associated with the promotion of Th1 immune response which is associated with protection against TB. Although this aspect remains controversial at present due to the lack of established correlates of protection, currently, there are different prophylactic, diagnostic, and immunotherapeutic approaches in which IFNs play an important role. This review summarizes the main aspects related with the biology of IFNs, mainly associated with TB, as well as presents the main applications of these cytokines related to prophylaxis, diagnosis, and immunotherapy of TB.

• epitope mapping
• interleukin-23
• protein-protein interaction
• surface plasmon resonance (spr)
• hydrogen/deuterium exchange mass spectrometry
• fast photochemical oxidation of proteins
• computer modeling
• mutagenesis
• monoclonal antibody
• biotechnology

• Alanine/metabolism
• Antibodies, Monoclonal/metabolism
• Antigen-Antibody Reactions
• Cloning, Molecular
• Deuterium Exchange Measurement
• Epitope Mapping/methods
• Epitopes/metabolism
• Immunoglobulin Fab Fragments/metabolism
• Interleukin-23/metabolism
• Mass Spectrometry
• Models, Molecular
• Mutagenesis
• Oxidation-Reduction
• Protein Binding

• P41 GM103422 NIGMS NIH HHS
• S10 OD016298 NIH HHS

• Dendritic cells
• IL-17
• PDE4
• PKA
• T cells
• cAMP

Although corticosteroid is a powerful anti-inflammatory drug that is used widely to control asthma, still severe asthmatics can develop steroid resistance. Airway fibroblasts are quite resistant to steroids during Idiopathic pulmonary fibrosis (IPF) and fibrosis in asthmatic lungs is not always controlled. Th-17 regulatory cytokine which are elevated in lung tissues of asthmatics were shown to enhance the survival of various types of cells. STAT factors are central to this anti-apoptotic function. However, it is not yet clear whether these cytokines contribute to steroid hypo-responsiveness in asthma. Therefore, in this study, we investigated the ability of Th-17 regulatory cytokines, specifically IL-21, IL22 and IL23, to protect structural airway cells against dexamethasone-induced apoptosis.

Primary human fibroblasts, ASM cells, and lung endothelial cells line were treated with IL-21, IL-22, and IL-23 cytokines before incubation with dexamethasone and the level of apoptosis was determined by measuring cellular Annexin-V using Flow cytometry.

Our data indicated that treatment with Th-17 regulatory cytokines was effective in inhibiting induced apoptosis for both fibroblasts and endothelial cells but not ASM cells. STAT3 phosphorylation levels were also upregulated in fibroblasts and endothelial upon treatment with these cytokines. Interestingly, inhibiting STAT3 phosphorylation abrogated IL-21, IL-22, and IL-23 anti-apoptotic effect on fibroblasts and endothelial cells.

This data suggest that Th-17 regulatory cytokines may play a critical role in regulating the survival of fibroblasts during asthma, IPF as well as other chronic lung inflammatory diseases leading to enhanced fibrosis. Accordingly, findings of this paper may pave the way for more extensive research on the role of these regulatory cytokines in fibrosis development in various chronic inflammatory diseases.

• biotherapeutics
• hydrogen/deuterium exchange
• interleukins
• mass spectrometry
• protein binding
• protein–protein interactions
• structure

• Chinese Han male population
• Gout
• IL-23R
• rs7517847

• Adjuvant
• CpG ODN
• IFN-γ
• STING
• TLR
• cGAMP

Cytokine signals are essential for generating a robust and specialized immune response. These signals are typically transmitted via canonical STAT homodimers. However, the number of STAT molecules utilized by cytokine signaling cascades within immune cells are limited, and so the mechanism used to deliver complex signals remains elusive. Heterodimerization of STAT proteins is one potential mechanism for signals to be modified downstream of the receptor and may play an important role in dictating the targets of specific cytokine signaling. In this review, we discuss our current understanding of the prevalence of STAT heterodimers, how they are formed and what their physiologic role may be in vivo.

• STAT
• cytokine
• heterodimer
• homodimer
• signaling

Human Immunodeficiency Virus (HIV) and Schistosomiasis co-infection is common among residents at the shores of Lake Victoria in Kenya. About 36% of this population initiating antiretroviral therapy (ART) experience Immune Reconstitution Inflammatory Syndrome (IRIS) that complicates recovery. Several IL-23R alleles have been associated with susceptibility to both autoimmune and inflammatory diseases through T-helper type 17 (TH₁₇) cells. However, whether or not variants within the IL-23R increase susceptibility to IRIS in western Kenya is unknown. The objective of the current study was to determine the association between IL-23R gene polymorphisms, CD4+ cell counts and HIV RNA levels and IRIS in HIV and Schistosoma mansoni co-infected patients undergoing highly active anti-retroviral therapy (HAART).

A three-month case–control study was conducted on antiretroviral naïve schistosomiasis/HIV co-infected fishermen starting HAART in Uyoma Rarieda, Siaya County, Kenya. Seventy one patients were sampled at baseline and followed up for three months, to establish if they developed Schistosoma-related IRIS. In addition, the CD4+ cell counts and HIV RNA levels were determined in pre- and post-administration of HAART. Variations at five polymorphic sites of IL-23R (rs1884444, rs11465754, rs6682925, rs7530511 and rs7539625) based on >10% minor allele frequency in Yoruban reference population was determined using Allelic Discrimination Assay. The association between the five variants and susceptibility to IRIS was determined using logistic regression while controlling for potential confounders. In addition, the functional differences between the baseline CD4 + Cell counts and viral loads were determined using medians while across IL-23R genotypes were determined using Kruskal-Wallis tests.

Overall, 26 (36.6%) patients developed schistosomiasis-associated IRIS at a median age of 35.5 years. Carriage of the TT genotype at the non-synonymous rs1884444 T > G relative to GG, was associated with a decreased risk of schistosomiasis-associated IRIS (OR, 0.25, 95% CI, 0.07-0.96, P = 0.043) while both baseline CD4+ cell counts and viral loads had no association with IRIS.

These findings indicate that the non-synonymous variant rs1884444 T > G of IL-23R is associated with a decreased risk to schistosomiasis-associated IRIS. However, additional studies in a larger cohort and with an all inclusive polymorphic variants in the synonymous and non-synonymous regions need to be evaluated.

The use of micelle aggregates formed from peptide amphiphiles (PAs) as potential synthetic self-adjuvant vaccines to treat Herpes simplex virus (HSV) infection are reported here. The PAs were based on epitopes gB_409–505 and gD_301–309, selected from HSV envelope glycoprotein B (gB) and glycoprotein D (gD), that had their N-terminus modified with hydrophobic moieties containing two C18 hydrocarbon chains. Pure and mixed micelles of gB and/or gD peptide epitopes were easily prepared after starting with the synthesis of corresponding PAs by solid phase methods. Structural characterization of the aggregates confirmed that they were sufficiently stable and compatible with in vivo use: critical micelle concentration values around 4.0 ⋅ 10⁻⁷ mol ⋅ Kg⁻¹; hydrodynamic radii (R_H) between 50–80 nm, and a zeta potential (ζ) around − 40 mV were found for all aggregates. The in vitro results indicate that both peptide epitopes and micelles, at 10 μM, triggered U937 and RAW 264.7 cells to release appreciable levels of cytokines. In particular, interleukin (IL)-23-, IL-6-, IL-8- or macrophage inflammatory protein (MIP)-2-, and tumor necrosis factor (TNF)-α-release increased considerably when cells were treated with the gB-micelles or gD-micelles compared with the production of the same cytokines when the stimulus was the single gB or gD peptide.

• HSV
• epitopes
• self-adjuvant vaccine

• Animals
• Brain Neoplasms/immunology
• Brain Neoplasms/therapy
• Dendritic Cells/immunology
• Glioma/immunology
• Glioma/therapy
• Humans
• Immunotherapy/methods