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Interleukin-6 (IL-6) is vital for competent anti-microbial host defense. Mice deficient in IL-6 showed an inability to appropriately control bacterial peritonitis (5×108 cfu Staphylococcus epidermidis) and displayed both increased dissemination and reduced bacterial clearance. This response was reversed through local reconstitution of IL-6 trans-signaling using a chimeric sIL-6R-IL-6 fusion protein (termed HDS). Administration of HDS (10–1000ng/ml) to infected IL-6−/− mice promoted bacterial clearance and reduced bacteremia in a dose-dependent fashion. This response was associated with improved resolution of the acute phase response and a more rapid normalization of body temperature. To define the mechanisms governing IL-6 involvement in anti-microbial immunity, we first developed an ex vivo flow cytometric assay to simultaneously monitor neutrophil respiratory burst and phagocytosis. Bacterial stimulation of circulating blood neutrophils from IL-6−/− and IL-6R−/− mice showed comparable effector function to that displayed by WT controls. Thus, IL-6 deficiency is not associated with an inherent defect in neutrophil function. However, evaluation of infiltrating neutrophils isolated by lavage from the peritoneal cavity of infected IL-6−/− and IL-6R−/− mice showed significantly reduced respiratory burst and phagocytic activity. Interleukin-6 therefore controls responses local to the site of infection and is consistent with the activation of non-hematopoietic stromal cells by IL-6 and sIL-6R. In human peritoneal mesothelial cells and peritoneal membranes from infected mice, IL-6 trans-signaling promoted cyclooxygenase-2 (COX2) expression. Blockade of IL-6 signaling in infected WT mice with the antagonist sgp130 or anti-IL-6R antibodies inhibited peritoneal COX2 expression. Mass spectrometry for the COX2 products, prostaglandin-E2 (PGE2) prostaglandin-D2 (PGD2) in lavage samples from infected mice showed that the generation of PGD2, but not PGE2, was impaired in IL-6 deficiency. Here, PGD2 levels correlated with the number of infiltrating neutrophils undergoing respiratory burst. These studies suggest IL-6 signaling regulates the effector characteristics of infiltrating neutrophils through local control of immuno-regulatory prostaglandin production. [ABSTRACT FROM AUTHOR]

Evaluation of joint tissue from early inflammatory arthritis patients through ultrasound-guided synovial biopsy has enabled disease classification based on local pathology. For example, the disease can be classed as fibroblast-, myeloid- or lymphoid-driven. Lymphoid histopathology can be further divided into patients displaying either diffuse infiltrates, or ectopic lymphoid-like structures (ELS) reminiscent of the follicular compartments in secondary lymphoid organs. Approximately 25% of rheumatoid arthritis (RA) patients develop ELS and display severe symptoms associated with local immune cell priming and autoantibody production. However, cytokine control of ELS development in inflammatory arthritis is poorly defined. Interleukin (IL)-27 is a negative regulator of adaptive immune responses. To investigate the role of IL-27 in inflammatory arthritis, wild type (WT) and IL-27 receptor (IL-27R)-deficient mice were exposed to antigen-induced arthritis. IL-27R-deficient mice developed exacerbated inflammatory arthritis, displaying increased synovial infiltrate, hypertrophy and bone erosions. Heightened peripheral T H 17- and B-cell responses in IL-27R-deficiency were reflected in increased serum IL-17 levels and antigen-specific IgG titers. Strikingly, IL-27R-deficient mice developed synovial histopathology reminiscent of RA patients with ELS, comprising synovial lymphoid aggregates with distinct T-cell (CD3+), B-cell (B220+) and DC (F/480+, CD21+) areas that were absent in WT mice. Development of lymphoid aggregates was associated with elevated synovial expression of homeostatic chemokines that promote ectopic lymphoneogenesis (e.g. Cxcl13, Ccl21) and the transcriptional regulator Bcl-6, which is involved in germinal center organization and functional regulation. Ectopic lymphoneogenesis in IL-27R-deficient mice was not associated with an increase in synovial IL-6 or IL-21 expression. Studies in clinical RA patients reflect our experimental outcomes and reveal reduced synovial IL-27 expression in patients with joint histopathology comprising ELS compared to patients with diffuse lymphocytic infiltrates. Thus, IL-27 may negatively regulate the formation of ELS in human pathologies such as RA and represents a potential biomarker of synovial histopathology in early RA. [ABSTRACT FROM AUTHOR]

In addition to its widely recognized role as an anti-inflammatory cytokine, interleukin (IL)-10 is emerging as a potential regulator of the hypothalamic–pituitary–adrenal (HPA) axis, a major part of the neuroendocrine system that controls reaction to stress. The HPA axis is a homeostatic feedback process that produces glucocorticosteroids and hormones that govern digestion, mood and certain immune responses. In rheumatoid arthritis (RA), appropriate control of the HPA axis is often lost and contributes to the incidence of fatigue and depression in patients. In parallel, both RA and depression have been linked to abnormal IL-10 production. In IL-10 deficient (IL-10KO) mice, the inflammatory histopathology associated with antigen-induced arthritis (AIA) is enhanced compared to wild-type (WT) controls. However, little is known about the interplay between the immune and neuroendocrine systems during inflammatory arthritis. Here, we consider IL-10 production in neuroendocrine tissues as a potential mediator of HPA axis function and behavior during arthritis. IL-10KO and WT mice were examined by open field test (OFT) to assess locomotor and exploratory activity following AIA onset. HPA tissue samples, assessed for alterations in gene expression, were harvested at Day 3 and Day 28 of AIA. Compared to WT, IL-10KO mice showed elevated adrenal adrenocorticotropic hormone receptor and pituitary pro-opiomelanocortin expression at Day 3. Coinciding with these HPA axis abnormalities, IL-10KO mice displayed reduced locomotor activity, and spent less time exploring the center of the arena (index of anxious-like behavior). While OFT behaviors in both genotypes returned to baseline by Day 7, joint degeneration progressed. At Day 28, severe joint histopathology was concurrent with elevated hypothalamic glucocorticoid receptor and melatonin receptor 1a expression in IL-10KO mice. These data indicate that the induction of disease coincides with fluctuations in the control of the HPA axis and emphasize a regulatory role for the inflammatory cytokine IL-10 during inflammatory arthritis. [ABSTRACT FROM AUTHOR]