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TLR cross-talk specifically regulates cytokine production by B cells from chronic inflammatory disease patients.

ABSTRACT: Chronic systemic inflammation links periodontal disease and diabetes to increased incidence of serious comorbidities. Activation of TLRs, particularly TLR2 and TLR4, promotes chronic systemic inflammation. Human B cells have been generally thought to lack these TLRs. However, recent work showed that an increased percentage of circulating B cells from inflammatory disease patients express TLR2 and TLR4, and that TLR engagement on B cells resulted in unexpected changes in gene expression. New data show that B cells from inflammatory disease patients secrete multiple cytokines in response to different classes of TLR ligands. Furthermore, the B cell response to combinations of TLR ligands is cytokine- and ligand-specific. Some cytokines (IL-1beta and IL-10) are predominantly regulated by TLR4, but others (IL-8 and TNF-alpha) are predominantly regulated by TLR2, due in part to TLR-dictated changes in transcription factor/promoter association. TLR2 and TLR9 also regulate B cell TLR4 expression, demonstrating that TLR cross-talk controls B cell responses at multiple levels. Parallel examination of B cells from periodontal disease and diabetes patients suggested that outcomes of TLR cross-talk are influenced by disease pathology. We conclude that disease-associated alteration of B cell TLR responses specifically regulates cytokine production and may influence chronic inflammation.

SUBMITTER: Jagannathan M

PROVIDER: S-EPMC2851147 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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TLR cross-talk specifically regulates cytokine production by B cells from chronic inflammatory disease patients.

Jagannathan Madhumita M Hasturk Hatice H Liang Yanmei Y Shin Hyunjin H Hetzel Jeremy T JT Kantarci Alpdogan A Rubin Daniel D McDonnell Marie E ME McDonnell Marie E ME Van Dyke Thomas E TE Ganley-Leal Lisa M LM Nikolajczyk Barbara S BS

Journal of immunology (Baltimore, Md. : 1950) 20091116 11

Chronic systemic inflammation links periodontal disease and diabetes to increased incidence of serious comorbidities. Activation of TLRs, particularly TLR2 and TLR4, promotes chronic systemic inflammation. Human B cells have been generally thought to lack these TLRs. However, recent work showed that an increased percentage of circulating B cells from inflammatory disease patients express TLR2 and TLR4, and that TLR engagement on B cells resulted in unexpected changes in gene expression. New data ...[more]

PMID: 19917698

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Project description:BACKGROUND: Development in systems biology research has accelerated in recent years, and the reconstructions for molecular networks can provide a global view to enable in-depth investigation on numerous system properties in biology. However, we still lack a systematic approach to reconstruct the dynamic protein-protein association networks at different time stages from high-throughput data to further analyze the possible cross-talks among different signaling/regulatory pathways. METHODS: In this study we integrated protein-protein interactions from different databases to construct the rough protein-protein association networks (PPANs) during TNFalpha-induced inflammation. Next, the gene expression profiles of TNFalpha-induced HUVEC and a stochastic dynamic model were used to rebuild the significant PPANs at different time stages, reflecting the development and progression of endothelium inflammatory responses. A new cross-talk ranking method was used to evaluate the potential core elements in the related signaling pathways of toll-like receptor 4 (TLR-4) as well as receptors for tumor necrosis factor (TNF-R) and interleukin-1 (IL-1R). RESULTS: The highly ranked cross-talks which are functionally relevant to the TNFalpha pathway were identified. A bow-tie structure was extracted from these cross-talk pathways, suggesting the robustness of network structure, the coordination of signal transduction and feedback control for efficient inflammatory responses to different stimuli. Further, several characteristics of signal transduction and feedback control were analyzed. CONCLUSIONS: A systematic approach based on a stochastic dynamic model is proposed to generate insight into the underlying defense mechanisms of inflammation via the construction of corresponding signaling networks upon specific stimuli. In addition, this systematic approach can be applied to other signaling networks under different conditions in different species. The algorithm and method proposed in this study could expedite prospective systems biology research when better experimental techniques for protein expression detection and microarray data with multiple sampling points become available in the future.

Project description:The role of Interleukin(IL)-6 in the pathogenesis of joint and systemic inflammation in rheumatoid arthritis (RA) and systemic juvenile idiopathic arthritis (s-JIA) has been clearly demonstrated. However, the mechanisms by which IL-6 contributes to the pathogenesis are not completely understood. This study investigates whether IL-6 affects, alone or upon toll like receptor (TLR) ligand stimulation, the production of inflammatory cytokines and chemokines in human peripheral blood mononuclear cells (PBMCs), synovial fluid mononuclear cells from JIA patients (SFMCs) and fibroblast-like synoviocytes from rheumatoid arthritis patients (RA synoviocytes) and signalling pathways involved. PBMCs were pre-treated with IL-6 and soluble IL-6 Receptor (sIL-6R). SFMCs and RA synoviocytes were pre-treated with IL-6/sIL-6R or sIL-6R, alone or in combination with Tocilizumab (TCZ). Cells were stimulated with LPS, S100A8-9, poly(I-C), CpG, Pam2CSK4, MDP, IL-1?. Treatment of PBMCs with IL-6 induced production of TNF-?, CXCL8, and CCL2, but not IL-1?. Addition of IL-6 to the same cells after stimulation with poly(I-C), CpG, Pam2CSK4, and MDP induced a significant increase in IL-1? and CXCL8, but not TNF-? production compared with TLR ligands alone. This enhanced production of IL-1? and CXCL8 paralleled increased p65 NF-?B activation. In contrast, addition of IL-6 to PBMCs stimulated with LPS or S100A8-9 (TLR-4 ligands) led to reduction of IL-1?, TNF-? and CXCL8 with reduced p65 NF-?B activation. IL-6/IL-1? co-stimulation increased CXCL8, CCL2 and IL-6 production. Addition of IL-6 to SFMCs stimulated with LPS or S100A8 increased CXCL8, CCL2 and IL-1? production. Treatment of RA synoviocytes with sIL-6R increased IL-6, CXCL8 and CCL2 production, with increased STAT3 and p65 NF-?B phosphorylation. Our results suggest that IL-6 amplifies TLR-induced inflammatory response. This effect may be relevant in the presence of high IL-6 and sIL-6R levels, such as in arthritic joints in the context of stimulation by endogenous TLR ligands.

Dataset Information

TLR cross-talk specifically regulates cytokine production by B cells from chronic inflammatory disease patients.

Publications

TLR cross-talk specifically regulates cytokine production by B cells from chronic inflammatory disease patients.

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