SummaryExpression of the macrophage mannose receptor is inhibited by interferon y (IFN-30, a T helper type 1 (Th-1)-derived lymphokine. Interleukin 4 (I1:4), a Th-2 lymphocyte product, upregulates major histocompatibility class II antigen expression but inhibits inflammatory cytokine production by macrophages. We have studied the effect of Ib4 on expression of the macrophage mannose receptor (MMR) by elicited peritoneal macrophages. We found that recombinant murine Ib4 enhances MMR surface expression (10-fold) and activity (15-fold), as measured by the respective binding and degradation of 12SI-mannose-bovine serum albumin. Polymerase chain reaction analysis of cDNAs from purified primary macrophage populations revealed that MMR, but not lysozyme or tumor necrosis factor ~ mRNA levels were markedly increased by IL-4. The above effects were associated with morphologic changes. These data establish II-4 as a potent and sdective enhancer of murine MMR activity in vitro. IL-4 induces inflammatory macrophages to adopt an alternative activation phenotype, distinct from that induced by IFN-% characterized by a high capacity for endocytic clearance of mannosylated ligands, enhanced (albeit restricted) MHC class II antigen expression, and reduced proinflammatory cytokine secretion. The macrophage mannose receptor (MMR) (previously called the mannosyl fucosyl receptor [MFR]) is an important phagocytic receptor mediating the binding and ingestion of micro-organisms with surface mannose residues and soluble mannose-containing glycoproteins. It is expressed on resident and elicited peritoneal macrophages and alveolar macrophages, not expressed on monocytes, and at low levels on Bacill~-Calmette-Guerin (BCG)-or IFN-3~-activated macrophages (1). Therefore, the MMR is a marker of the resident and elicited, but not IFN-y-activated, macrophage phenotype. MMR activity is increased by steroids and IFN-ol and -fl, and is inversely correlated with MHC class II antigen expression, which is induced on immunologically stimulated macrophages and used as a marker of activation. ID4, predominantly produced by activated Th cells of the type 2 phenotype and non-B, non-T, FcER + cells, has pleiotropic effects on a variety of immune and nonimmune cells. As it induces the expression of MHC class II antigen on B cells and monocytes, and enhances macrophage tumoricidal activity, it has been described as a macrophage-activating factor (2). However, the tumoricidal activity is confined to selected target cell lines, and only HLA-DR and HLA-DP but not HLA-DQ MHC class II molecules are induced by ID4. In addition, IL-4 induces MHC class II antigen expression on restricted macrophage populations. In contrast, IFN-3' induces all three class II molecules on most if not all macrophages (3, 4). Furthermore, Ib4 inhibits the expression of pro-inflammatory cytokine genes such as I1:1, TNF, and I1:8, and synergizes with steroids to inhibit macrophage proinflammatory activity (5-9). In addition, I1:4 inhibits superoxide anion release from PMA or zymosan-treat...

Interferon-gamma (IFN-gamma) is a pleiotrophic cytokine with immunomodulatory effects on a variety of immune cells. Mice with a targeted disruption of the IFN-gamma gene were generated. These mice developed normally and were healthy in the absence of pathogens. However, mice deficient in IFN-gamma had impaired production of macrophage antimicrobial products and reduced expression of macrophage major histocompatibility complex class II antigens. IFN-gamma-deficient mice were killed by a sublethal dose of the intracellular pathogen Mycobacterium bovis. Splenocytes exhibited uncontrolled proliferation in response to mitogen and alloantigen. After a mixed lymphocyte reaction, T cell cytolytic activity was enhanced against allogeneic target cells. Resting splenic natural killer cell activity was reduced in IFN-gamma-deficient mice. Thus, IFN-gamma is essential for the function of several cell types of the murine immune system.

Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are complex chronic inflammatory conditions of the gastrointestinal tract that are driven by perturbed cytokine pathways. Anti-tumor necrosis factor-α (TNF) antibodies are a mainstay therapeutic approach for IBD. However, up to 40% of patients are non-responsive to anti-TNF agents, and identifying alternative therapeutic targets is a priority. Here we show that expression of the cytokine Oncostatin M (OSM) and its receptor (OSMR) is increased in the inflamed intestine of IBD patients compared to healthy controls, and correlates closely with histopathological disease severity. OSMR is expressed in non-hematopoietic, non-epithelial intestinal stromal cells, which respond to OSM by producing various pro-inflammatory molecules including interleukin-6 (IL-6), the leukocyte adhesion factor ICAM-1, and chemokines that attract neutrophils, monocytes, and T cells. In an animal model of anti-TNF resistant intestinal inflammation, genetic deletion or pharmacological blockade of OSM significantly attenuates colitis. Furthermore, high pre-treatment OSM expression is strongly associated with failure of anti-TNF therapy based on analysis of over 200 IBD patients, including two cohorts from phase 3 clinical trials of infliximab and golimumab. OSM is thus a potential biomarker and therapeutic target for IBD, with particular relevance for anti-TNF resistant patients.

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Histological remission is a target distinct from endoscopic mucosal healing in UC and better predicts lower rates of corticosteroid use and acute severe colitis requiring hospitalisation, over a median of 6 years of follow-up. Our findings support the inclusion of histological indices in both UC clinical trials and practice, towards a target of 'complete remission'.

During gram-negative bacterial infections, lipopolysaccharide (LPS) stimulates primed macrophages (Mφ) to release inflammatory mediators such as tumor necrosis factor (TNF)-α, which can cause hypotension, organ failure, and often death. Several different receptors on Mφ have been shown to bind LPS, including the type A scavenger receptor (SR-A). This receptor is able to bind a broad range of polyanionic ligands such as modified lipoproteins and lipoteichoic acid of gram-positive bacteria, which suggests that SR-A plays a role in host defense. In this study, we used mice lacking the SR-A (SRKO) to investigate the role of SR-A in acquired immunity using a viable bacillus Calmette Guérin (BCG) infection model. We show that activated Mφ express SR-A and that this molecule is functional in assays of adhesion and endocytic uptake. After BCG infection, SRKO mice are able to recruit Mφ to sites of granuloma formation where they become activated and restrict BCG replication. However, infected mice lacking the SR-A are more susceptible to endotoxic shock and produce more TNF-α and interleukin-6 in response to LPS. In addition, we show that an antibody which blocks TNF-α activity reduces LPS-induced mortality in these mice. Thus SR-A, expressed by activated Mφ, plays a protective role in host defense by scavenging LPS as well as by reducing the release by activated Mφ of proinflammatory cytokines. Modulation of SR-A may provide a novel therapeutic approach to control endotoxic shock.

Background & AimsInteractions between commensal microbes and the immune system are tightly regulated and maintain intestinal homeostasis, but little is known about these interactions in humans. We investigated responses of human CD4+ T cells to the intestinal microbiota. We measured the abundance of T cells in circulation and intestinal tissues that respond to intestinal microbes and determined their clonal diversity. We also assessed their functional phenotypes and effects on intestinal resident cell populations, and studied alterations in microbe-reactive T cells in patients with chronic intestinal inflammation.MethodsWe collected samples of peripheral blood mononuclear cells and intestinal tissues from healthy individuals (controls, n = 13−30) and patients with inflammatory bowel diseases (n = 119; 59 with ulcerative colitis and 60 with Crohn’s disease). We used 2 independent assays (CD154 detection and carboxy-fluorescein succinimidyl ester dilution assays) and 9 intestinal bacterial species (Escherichia coli, Lactobacillus acidophilus, Bifidobacterium animalis subsp lactis, Faecalibacterium prausnitzii, Bacteroides vulgatus, Roseburia intestinalis, Ruminococcus obeum, Salmonella typhimurium, and Clostridium difficile) to quantify, expand, and characterize microbe-reactive CD4+ T cells. We sequenced T-cell receptor Vβ genes in expanded microbe-reactive T-cell lines to determine their clonal diversity. We examined the effects of microbe-reactive CD4+ T cells on intestinal stromal and epithelial cell lines. Cytokines, chemokines, and gene expression patterns were measured by flow cytometry and quantitative polymerase chain reaction.ResultsCirculating and gut-resident CD4+ T cells from controls responded to bacteria at frequencies of 40−4000 per million for each bacterial species tested. Microbiota-reactive CD4+ T cells were mainly of a memory phenotype, present in peripheral blood mononuclear cells and intestinal tissue, and had a diverse T-cell receptor Vβ repertoire. These cells were functionally heterogeneous, produced barrier-protective cytokines, and stimulated intestinal stromal and epithelial cells via interleukin 17A, interferon gamma, and tumor necrosis factor. In patients with inflammatory bowel diseases, microbiota-reactive CD4+ T cells were reduced in the blood compared with intestine; T-cell responses that we detected had an increased frequency of interleukin 17A production compared with responses of T cells from blood or intestinal tissues of controls.ConclusionsIn an analysis of peripheral blood mononuclear cells and intestinal tissues from patients with inflammatory bowel diseases vs controls, we found that reactivity to intestinal bacteria is a normal property of the human CD4+ T-cell repertoire, and does not necessarily indicate disrupted interactions between immune cells and the commensal microbiota. T-cell responses to commensals might support intestinal homeostasis, by producing barrier-protective cytokines and providing a large pool of T cells that react to pathogens.

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