• Gametogenesis
• Gene interaction
• Knockout mice
• Pramel1
• Pramex1
• Retinoic acid
• Sertoli-cell only

• 1472409 Pennsylvania Department of Health
• The Sarah Chinn Kalser Faculty Research Assistance Endowment College of Agricultural Sciences, Pennsylvania State University
• R21HD114044 National Institute of Health

• Glucose
• Insulin
• Insulin resistance
• Microbiome
• Microbiota
• Obesity

• Animals
• Mice
• Insulin Resistance
• Lipopolysaccharides
• NLR Proteins
• Inflammation
• Diabetes Mellitus
• Microbiota
• Obesity/metabolism

Nucleotide-binding oligomerization domain 1 (NOD1) receptor and Toll-like receptor 4 (TLR4) belong to the family of pattern recognition receptors. Interactions between these receptors profoundly shape the innate immune responses. We previously demonstrated that co-stimulation of peripheral blood mononuclear cells (PBMCs) with D-glutamyl-meso-diaminopimelic acid (iE-DAP)-based NOD1 agonists and lipopolysaccharide (LPS), a TLR4 agonist, synergistically increased the cytokine production. Herein, we postulate that stimulation of NOD1 alone or a combined stimulation of NOD1 and TLR4 could also strengthen PBMC-mediated cytotoxicity against cancer cells. Initially, an in-house library of iE-DAP analogs was screened for NOD1 agonist activity to establish their potency in HEK-Blue NOD1 cells. Next, we showed that our most potent NOD1 agonist SZZ-38 markedly enhanced the LPS-induced cytokine secretion from PBMCs, in addition to PBMC- and natural killer (NK) cell-mediated killing of K562 cancer cells. Activation marker analysis revealed that the frequencies of CD69⁺, CD107a⁺, and IFN-γ⁺ NK cells are significantly upregulated following NOD1/TLR4 co-stimulation. Of note, SZZ-38 also enhanced the IFN-γ-induced PBMC cytotoxicity. Overall, our findings provide further insight into how co-engagement of two pathways boosts the non-specific immune response and attest to the importance of such interplay between NOD1 and TLR4.

• Javna Agencija za Raziskovalno Dejavnost RS

• mechanism of action
• postbiotics
• probiotics

• Bacteria
• Diet
• Dysbiosis/microbiology
• Gastrointestinal Microbiome/physiology
• Host Microbial Interactions/drug effects
• Humans
• Microbiota/physiology
• Prebiotics/microbiology
• Probiotics/metabolism
• Probiotics/pharmacology
• Symbiosis/physiology

In 3-month bone marrow transplants of CBA mice from bone marrow donors receiving single injections of TLR-4 ligand (LPS) or NOD-2 ligand (muramyl dipeptide, MDP) 24 h before transplantation, an increase in the total number of MSCs (by 2.6 and 1.9 times, respectively), as well as a slight increase in the number of nuclear cells and the mass of bone capsules (by 1.3 and 1.2 times) were observed. After combined administration of MDР and LPS to donors, the total content of MSCs in the grafts was higher by 1.6 times in comparison with the total result of their isolated administration (and by 7.2 times in comparison with the control). At the same time, the concentration of osteogenic MSCs in the grafts of all groups was almost the same and corresponded to the control level. The number of nuclear cells and the mass of bone capsules of the grafts after combined administration of LPS and MDP were close (~80%) to the sum of the results of their isolated administration. These findings suggest that activation of the stromal tissue and the success of bone marrow transplantation depend on the intensity of innate immune responses. These data can be useful for the development of optimal methods of tissue transplantation.

• MSCs
• NLR and TLR ligands
• immune response
• transplantation

• dendritic cells
• il-1r
• il-1 family of cytokines
• tnf superfamily
• auto-immunity
• memory t cells
• th17 cells
• systemic inflammation

• Adaptive Immunity
• Animals
• Cytokines/metabolism
• Humans
• Immunity, Innate
• Immunologic Memory
• Inflammation/immunology
• Memory T Cells/immunology
• Myeloid Cells/immunology
• Signal Transduction

• R01 AI123176 NIAID NIH HHS
• R01 AI155426 NIAID NIH HHS
• T32 AI005284 NIAID NIH HHS

• Arabidopsis/cytology
• Arabidopsis/immunology
• Arabidopsis/microbiology
• Cell Death
• NADPH Oxidases/metabolism
• NLR Proteins/immunology
• Plant Cells/immunology
• Plant Cells/microbiology
• Plant Diseases/immunology
• Plant Diseases/microbiology
• Plant Immunity/immunology
• Protein Kinases/metabolism
• Pseudomonas fluorescens/immunology
• Pseudomonas syringae/immunology
• Pseudomonas syringae/pathogenicity
• Receptors, Pattern Recognition/immunology
• Signal Transduction/immunology

• European Research Council

• Aflatoxin B1
• Cell damage alleviation
• Chicken embryo primary cells
• Compound probiotics
• Mycotoxin-degradation enzyme

• Natural Science Foundation of Henan Province
• Xinxiang Key Scientific and Technological Project, China
• Henan Innovation and Demonstration Project, China

• Allergic asthma
• Dendritic cells
• Helicobacter pylori
• Helper T cells
• Protective effect
• Regulatory T cells

• Type I interferon
• chitosan
• diphtheria toxoid
• intranasal immunization
• vaccines

• collaboration
• innate immunity
• pattern recognition receptors
• synergy

• LPS
• Poly (I:C)
• TLR3 and TLR4 costimulation
• mice
• multipotent stromal cells (MSC)

• Acute kidney injury
• Ischemia/reperfusion injury
• NOD1
• NOD2
• TLR2

• Animals
• Humans
• Immunity, Innate
• Inflammation/metabolism
• Kidney/immunology
• Kidney/surgery
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Myeloid Cells/immunology
• Nod1 Signaling Adaptor Protein/genetics
• Nod1 Signaling Adaptor Protein/metabolism
• Nod2 Signaling Adaptor Protein/genetics
• Nod2 Signaling Adaptor Protein/metabolism
• Reperfusion Injury/metabolism
• Signal Transduction
• Toll-Like Receptor 2/genetics
• Toll-Like Receptor 2/metabolism

• R01 DK091136 NIDDK NIH HHS
• R01 DK113162 NIDDK NIH HHS

• Immunomodulation
• Interleukin-8
• NF-κB activation
• NOD1 antagonist
• NOD2 antagonist
• Tumor necrosis factor-α

• Anti-Inflammatory Agents/chemical synthesis
• Anti-Inflammatory Agents/pharmacology
• Anti-Inflammatory Agents/toxicity
• Benzimidazoles/chemical synthesis
• Benzimidazoles/pharmacology
• Benzimidazoles/toxicity
• Drug Design
• HEK293 Cells
• Humans
• Molecular Structure
• Nod1 Signaling Adaptor Protein/antagonists & inhibitors
• Nod2 Signaling Adaptor Protein/antagonists & inhibitors
• Structure-Activity Relationship

THP-1 cells express high levels of native functional nucleotide-binding oligomerization domain 1 (NOD1), NOD2, and Toll-like receptor 4 (TLR4) receptors, and have often been used for investigating the immunomodulatory effects of small molecules. We postulated that they would represent an ideal cell-based model for our study, the aim of which was to develop a new in vitro tool for functional characterization of NOD antagonists. NOD antagonists were initially screened for their effect on NOD agonist-induced interleukin-8 (IL-8) release. Next, we examined the extent to which the selected NOD antagonists block the NOD-TLR4 synergistic crosstalk by measuring the effect of NOD antagonism on tumor necrosis factor-α (TNF-α) secretion from doubly activated THP-1 cells. Overall, the results obtained indicate that pro-inflammatory cytokine secretion from THP-1 provides a valuable, simple and reproducible in vitro tool for functional characterization of NOD antagonists.

• IL-8
• NOD1 antagonist
• NOD2 antagonist
• THP-1
• TNF-α
• cytokines
• functional characterization
• immunomodulation

• Cell Survival
• Cytokines/biosynthesis
• Humans
• Inflammation Mediators/metabolism
• Nod1 Signaling Adaptor Protein/agonists
• Nod1 Signaling Adaptor Protein/antagonists & inhibitors
• Nod1 Signaling Adaptor Protein/metabolism
• Nod2 Signaling Adaptor Protein/agonists
• Nod2 Signaling Adaptor Protein/antagonists & inhibitors
• Nod2 Signaling Adaptor Protein/metabolism
• THP-1 Cells
• Toll-Like Receptor 4/metabolism

• NLR and TLR ligands
• immune response
• stromal cells

• NF-κB
• NOD1
• NOD2
• TLR4
• lipopolysaccharide
• muramyl dipeptide
• sepsis

• Infectious diseases
• Innate immunity
• Mucosal immunity
• Muropeptides
• NOD1
• NOD2

• Pathogen recognition
• TLR signaling
• Toll like receptor
• inflammation
• therapeutics
• tumor immunity

Caspases regulate cell death programs in response to environmental stresses, including infection and inflammation, and are therefore critical for the proper operation of the mammalian immune system. Caspase-8 is necessary for optimal production of inflammatory cytokines and host defense against infection by multiple pathogens including Yersinia, but whether this is due to death of infected cells or an intrinsic role of caspase-8 in TLR-induced gene expression is unknown. Caspase-8 activation at death signaling complexes results in its autoprocessing and subsequent cleavage and activation of its downstream apoptotic targets. Whether caspase-8 activity is also important for inflammatory gene expression during bacterial infection has not been investigated. Here, we report that caspase-8 plays an essential cell-intrinsic role in innate inflammatory cytokine production in vivo during Yersinia infection. Unexpectedly, we found that caspase-8 enzymatic activity regulates gene expression in response to bacterial infection as well as TLR signaling independently of apoptosis. Using newly-generated mice in which caspase-8 autoprocessing is ablated (Casp8^DA/DA), we now demonstrate that caspase-8 enzymatic activity, but not autoprocessing, mediates induction of inflammatory cytokines by bacterial infection and a wide variety of TLR stimuli. Because unprocessed caspase-8 functions in an enzymatic complex with its homolog cFLIP, our findings implicate the caspase-8/cFLIP heterodimer in control of inflammatory cytokines during microbial infection, and provide new insight into regulation of antibacterial immune defense.

TLR signaling induces expression of key inflammatory cytokines and pro-survival factors that facilitate control of microbial infection. TLR signaling can also engage cell death pathways through activation of enzymes known as caspases. Caspase-8 activates apoptosis in response to infection by pathogens that interfere with NF-κB signaling, including Yersinia, but has also recently been linked to control of inflammatory gene expression. Pathogenic Yersinia can cause severe disease ranging from gastroenteritis to plague. While caspase-8 mediates cell death in response to Yersinia infection as well as other signals, its precise role in gene expression and host defense during in vivo infection is unknown. Here, we show that caspase-8 activity promotes cell-intrinsic cytokine expression, independent of its role in cell death in response to Yersinia infection. Our studies further demonstrate that caspase-8 enzymatic activity plays a previously undescribed role in ensuring optimal TLR-induced gene expression by innate cells during bacterial infection. This work sheds new light on mechanisms that regulate essential innate anti-bacterial immune defense.

• Animals
• Apoptosis
• Caspase 8/immunology
• Caspase 8/metabolism
• Cytokines/biosynthesis
• Disease Models, Animal
• Enzyme-Linked Immunosorbent Assay
• Flow Cytometry
• Gene Expression Regulation/immunology
• Gene Knockdown Techniques
• Immunity, Innate/immunology
• Mice
• Mice, Inbred C57BL
• Polymerase Chain Reaction
• Signal Transduction/immunology
• Toll-Like Receptors/immunology
• Yersinia Infections/immunology

• R01 AI108685 NIAID NIH HHS
• R01 AI103062 NIAID NIH HHS
• R01 AI083284 NIAID NIH HHS
• T32 AI060516 NIAID NIH HHS
• R21 AI117365 NIAID NIH HHS
• R21 AI109267 NIAID NIH HHS
• K12 GM081259 NIGMS NIH HHS
• R21 CA185681 NCI NIH HHS
• National Institute of Allergy and Infectious Diseases
• National Cancer Institute
• Burroughs Wellcome Fund

The influence of DNA vaccine formulations on immune responses in combination with adjuvants was investigated with the aim to increase cell-mediated immunity against plasmid DNA (pDNA) encoding Mycobacterium tuberculosis antigen 85A. Different ratios of pDNA with cationic trimethyl chitosan (TMC) nanoparticles were characterized for their morphology and physicochemical characteristics (size, zeta potential, loading efficiency and pDNA release profile) applied in vitro for cellular uptake studies and in vivo, to determine the dose-dependent effects of pDNA on immune responses. A selected pDNA/TMC nanoparticle formulation was optimized by the incorporation of muramyl dipeptide (MDP) as an immunostimulatory agent. Cellular uptake investigations in vitro showed saturation to a maximum level upon the increase in the pDNA/TMC nanoparticle ratio, correlating with increasing Th1-related antibody responses up to a definite pDNA dose applied. Moreover, TMC nanoparticles induced clear polarization towards a Th1 response, indicated by IgG2c/IgG1 ratios above unity and enhanced numbers of antigen-specific IFN-γ producing T-cells in the spleen. Remarkably, the incorporation of MDP in TMC nanoparticles provoked a significant additional increase in T-cell-mediated responses induced by pDNA. In conclusion, pDNA-loaded TMC nanoparticles are capable of provoking strong Th1-type cellular and humoral immune responses, with the potential to be further optimized by the incorporation of MDP.

• DNA vaccine
• N-trimethyl chitosan
• adjuvants
• cell-mediated immunity
• nanoparticles
• tuberculosis

Binding of pattern recognition receptors (PRRs) by pathogen-associated molecular patterns (PAMPs) activates innate immune responses and contributes to development of adaptive immunity. Simultaneous stimulation of different types of PRRs can have synergistic immunostimulatory effects resulting in enhanced production of molecules that mediate innate immunity such as inflammatory cytokines, antimicrobial peptides, etc. Here, we evaluated the impact of combined stimulation of PRRs from different families on adaptive immunity by generating alum-based vaccine formulations with ovalbumin as a model antigen and the Toll-like receptor 4 (TLR4) agonist MPLA and the Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) agonist MDP adsorbed individually or together on the alum-ovalbumin particles. Multiple in vitro and in vivo readouts of immune system activation all showed that while individual PRR agonists increased the immunogenicity of vaccines compared to alum alone, the combination of both PRR agonists was significantly more effective. Combined stimulation of TLR4 and NOD2 results in a stronger and broader transcriptional response in THP-1 cells compared to individual PRR stimulation. Immunostimulatory composition containing both PRR agonists (MPLA and MDP) in the context of the alum-based ovalbumin vaccine also enhanced uptake of vaccine particles by bone marrow derived dendritic cells (BMDCs) and promoted maturation (up-regulation of expression of CD80, CD86, MHCII) and activation (production of cytokines) of BMDCs. Finally, immunization of mice with vaccine particles containing both PRR agonists resulted in enhanced cellular immunity as indicated by increased proliferation and activation (IFN-γ production) of splenic CD4+ and CD8+ T cells following in vitro restimulation with ovalbumin and enhanced humoral immunity as indicated by higher titers of ovalbumin-specific IgG antibodies. These results indicate that combined stimulation of TLR4 and NOD2 receptors dramatically enhances activation of both the humoral and cellular branches of adaptive immunity and suggests that inclusion of agonists of these receptors in standard alum-based adjuvants could be used to improve the effectiveness of vaccination.

• Acetylmuramyl-Alanyl-Isoglutamine/immunology
• Adaptive Immunity
• Adjuvants, Immunologic
• Cell Line
• Humans
• Immunity, Cellular
• Immunity, Humoral
• Immunogenicity, Vaccine
• Lipid A/analogs & derivatives
• Lipid A/immunology
• Nod2 Signaling Adaptor Protein/immunology
• Ovalbumin/immunology
• Receptors, Pattern Recognition/agonists
• Receptors, Pattern Recognition/immunology
• Th1 Cells/immunology
• Toll-Like Receptor 4/immunology

• President's of the Russian Federation grant

• Alternate pathway
• Canonical pathway
• CellNOptR
• Cytocopter
• Cytoscape
• E3 ubiquitin ligase complex
• IKKß
• IKKα
• IRAK
• IκB
• MAP3K
• Mal cascade
• NEMO
• NFκB
• NIK
• RIP
• Signalling cross talk
• TLR pathway
• Ubiquitin proteasome signalling system

• Bovine
• Cytosolic nucleotide oligomerisation domain 1
• Immune response
• Neutrophils

• crosstalk
• infection
• innate immunity
• pattern recognition receptors
• signaling

The mammalian immune system is a dynamic multiscale system composed of a hierarchically organized set of molecular, cellular, and organismal networks that act in concert to promote effective host defense. These networks range from those involving gene regulatory and protein–protein interactions underlying intracellular signaling pathways and single‐cell responses to increasingly complex networks of in vivo cellular interaction, positioning, and migration that determine the overall immune response of an organism. Immunity is thus not the product of simple signaling events but rather nonlinear behaviors arising from dynamic, feedback‐regulated interactions among many components. One of the major goals of systems immunology is to quantitatively measure these complex multiscale spatial and temporal interactions, permitting development of computational models that can be used to predict responses to perturbation. Recent technological advances permit collection of comprehensive datasets at multiple molecular and cellular levels, while advances in network biology support representation of the relationships of components at each level as physical or functional interaction networks. The latter facilitate effective visualization of patterns and recognition of emergent properties arising from the many interactions of genes, molecules, and cells of the immune system. We illustrate the power of integrating ‘omics’ and network modeling approaches for unbiased reconstruction of signaling and transcriptional networks with a focus on applications involving the innate immune system. We further discuss future possibilities for reconstruction of increasingly complex cellular‐ and organism‐level networks and development of sophisticated computational tools for prediction of emergent immune behavior arising from the concerted action of these networks. WIREs Syst Biol Med 2015, 7:13–38. doi: 10.1002/wsbm.1288

This article is categorized under: 1

Analytical and Computational Methods > Computational Methods

Early sensing of pathogenic bacteria by the host immune system is important to develop effective mechanisms to kill the invader. Microbial recognition, activation of signaling pathways, and effector mechanisms are sequential events that must be highly controlled to successfully eliminate the pathogen. Host recognizes pathogens through pattern-recognition receptors (PRRs) that sense pathogen-associated molecular patterns (PAMPs). Some of these PRRs include Toll-like receptors (TLRs), nucleotide-binding oligomerization domain-like receptors (NLRs), retinoic acid-inducible gene-I- (RIG-I-) like receptors (RLRs), and C-type lectin receptors (CLRs). TLRs and NLRs are PRRs that play a key role in recognition of extracellular and intracellular bacteria and control the inflammatory response. The activation of TLRs and NLRs by their respective ligands activates downstream signaling pathways that converge on activation of transcription factors, such as nuclear factor-kappaB (NF-κB), activator protein-1 (AP-1) or interferon regulatory factors (IRFs), leading to expression of inflammatory cytokines and antimicrobial molecules. The goal of this review is to discuss how the TLRs and NRLs signaling pathways collaborate in a cooperative or synergistic manner to counteract the infectious agents. A deep knowledge of the biochemical events initiated by each of these receptors will undoubtedly have a high impact in the design of more effective strategies to control inflammation.

Gingivitis and periodontitis are initiated by inflammation caused by microorganisms. Pathogen-associated molecular patterns (PAMPs) from these microorganisms are recognized through various toll-like receptors (TLRs) and NOD-like receptors (NLRs). In this study, we have chosen five TLRs and two NLRs as representatives taking part in the recognition and inflammation process, along with a few of their signaling mediators including CD14, MYD88, and TRIF to compare their mRNA expression levels between healthy and diseased gingival tissues. This will provide deeper insight into the mechanisms underlying gingivitis and periodontitis. Understanding the mechanisms involved in the onset and progression of the periodontal diseases could greatly help in establishing effective ways for prevention and treatment of these diseases besides decreasing the risk factor for relevant systemic disorders.

Gingival tissue samples for mRNA extraction and cDNA synthesis were taken from patients with gingivitis and periodontitis and from healthy control subjects. Messenger RNA expression of all genes was assessed using real-time polymerase chain reaction (PCR).

Among the genes studied in different groups, only MYD88 mRNA expression was significantly higher in the periodontitis group compared to that of the controls. The expression level of this molecule was also significantly higher in patients with severe periodontitis compared to other patients and also compared to healthy individuals. In different tissues, positive significant correlations were observed between the mRNA expression levels of some genes.

Elevated mRNA levels of MYD88 in periodontitis might have a key role in the pathogenesis of this disease. Therefore, MYD88 may be a useful target for the therapy of this disease.

• Gingivitis
• inflammation
• mRNA expression
• periodontitis
• toll-like receptor

• C-type lectin
• Dendritic cell
• NF-κB
• Osteoclast Inhibitory Lectin Related Protein 2 (OCILRP2)
• TLR

• atherosclerosis
• endothelium
• intestinal immunity
• metabolic syndrome
• pulmonary immunity
• receptor-interacting protein 2
• septic shock

• Animals
• Anti-Inflammatory Agents/chemistry
• Anti-Inflammatory Agents/pharmacology
• Cardiovascular Diseases/drug therapy
• Cardiovascular Diseases/immunology
• Cardiovascular Diseases/metabolism
• Diabetes Mellitus, Type 2/drug therapy
• Diabetes Mellitus, Type 2/immunology
• Diabetes Mellitus, Type 2/metabolism
• Drug Design
• Humans
• Immunity, Innate/drug effects
• Inflammation/drug therapy
• Inflammation/immunology
• Inflammation/metabolism
• Molecular Targeted Therapy
• Nod1 Signaling Adaptor Protein/drug effects
• Nod1 Signaling Adaptor Protein/metabolism
• Signal Transduction/drug effects

• immune system
• inflammatory bowel disease
• intestinal microbiota
• mesalamine
• terminal restriction fragment length polymorphism

• 1,8-diazabicyclo[5.4.0]undec-7-ene
• 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate
• C12-iE-DAP
• DBU
• IL
• Immunomodulator
• Immunostimulant
• Immunotoxicity
• LPS
• LRR
• MAPK
• NF-κB
• NF-κB activation
• NLR
• Nod
• Nod-like receptor
• Nod1
• PAMP
• PBMC
• PRR
• RICK
• RIG
• SAR
• SEAP
• TBTU
• TLR
• TNF-α
• Toll-like receptor
• iE-DAP
• interleukin
• lauroyl-γ-d-glutamyl-meso-diaminopimelic
• leucine rich repeats
• lipopolysaccharide
• mitogen-activated protein kinase
• nuclear factor κB
• nucleotide-binding oligomerization domain protein
• pathogen-associated molecular pattern
• pattern recognition receptors
• peripheral blood mononuclear cells
• receptor-interacting serine-threonine kinase
• retinoic acid inducible gene
• secreted embryonic alkaline phosphatase
• structure/activity relationship
• tumor necrosis factor-α
• γ-d-Glutamyl-meso-diaminopimelic acid
• γ-d-glutamyl-meso-diaminopimelic acid

• t cells
• autoimmunity
• inflammation
• transgenic/knockout mice

• Animals
• Autoimmune Diseases/immunology
• Autoimmune Diseases/metabolism
• Autoimmune Diseases/pathology
• Chickens
• Ligands
• Lipopolysaccharides/metabolism
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Muramidase/genetics
• Peptidoglycan/metabolism
• Poly I-C/metabolism
• Th1 Cells/immunology
• Th1 Cells/metabolism
• Th1 Cells/pathology
• Th17 Cells/immunology
• Th17 Cells/metabolism
• Th17 Cells/pathology
• Toll-Like Receptor 2/metabolism
• Toll-Like Receptor 3/metabolism
• Toll-Like Receptor 4/metabolism
• Toll-Like Receptor 9/metabolism
• Toll-Like Receptors/metabolism
• Toll-Like Receptors/physiology

• ZIA EY000069-35 Intramural NIH HHS

• Adenocarcinoma/immunology
• Adenocarcinoma/metabolism
• Adenocarcinoma/pathology
• Animals
• Cell Line, Tumor
• Disease Progression
• Epithelial Cells/cytology
• Epithelial Cells/immunology
• Epithelial Cells/metabolism
• Humans
• Immunity, Innate
• Male
• Mice
• Mice, Inbred C57BL
• Nod1 Signaling Adaptor Protein/metabolism
• Nod1 Signaling Adaptor Protein/physiology
• Nod2 Signaling Adaptor Protein/metabolism
• Nod2 Signaling Adaptor Protein/physiology
• Prostate/cytology
• Prostate/immunology
• Prostate/metabolism
• Prostatic Neoplasms/immunology
• Prostatic Neoplasms/metabolism
• Prostatic Neoplasms/pathology

• Animals
• Cells, Cultured
• Endothelial Cells/immunology
• Endothelial Cells/metabolism
• Endothelial Cells/pathology
• Endothelium, Vascular/immunology
• Endothelium, Vascular/pathology
• Gram-Negative Bacteria/immunology
• Gram-Negative Bacteria/metabolism
• Humans
• MAP Kinase Kinase Kinases/immunology
• MAP Kinase Kinase Kinases/metabolism
• MAP Kinase Signaling System/immunology
• Male
• Muscle, Smooth, Vascular/immunology
• Muscle, Smooth, Vascular/pathology
• NF-kappa B/immunology
• NF-kappa B/metabolism
• Nod1 Signaling Adaptor Protein/agonists
• Nod1 Signaling Adaptor Protein/immunology
• Nod1 Signaling Adaptor Protein/metabolism
• Peptidoglycan/immunology
• Peptidoglycan/metabolism
• Rats
• Rats, Sprague-Dawley
• Receptor-Interacting Protein Serine-Threonine Kinase 2/immunology
• Receptor-Interacting Protein Serine-Threonine Kinase 2/metabolism
• Toll-Like Receptor 4/immunology
• Toll-Like Receptor 4/metabolism
• Vasculitis/immunology
• Vasculitis/metabolism
• Vasculitis/pathology
• Vasculitis/therapy
• p38 Mitogen-Activated Protein Kinases/immunology
• p38 Mitogen-Activated Protein Kinases/metabolism

• Wellcome Trust
• 0852551Z108/Z Wellcome Trust
• FS/09/017/26810 British Heart Foundation