Interleukin (IL)-1 signaling is required for the containment of infections with intracellular microorganisms, such as Listeria monocytogenes and Leishmania major. To determine the role of IL-1 in the host response to tuberculosis, we infected IL-1 type I receptor-deficient (IL-1R(-/-)) mice, in which IL-1 does not exert effects, with Mycobacterium tuberculosis. IL-1R(-/-) mice were more susceptible to pulmonary tuberculosis, as reflected by an increased mortality and an enhanced mycobacterial outgrowth in lungs and distant organs, which was associated with defective granuloma formation, containing fewer macrophages and fewer lymphocytes, whereas granulocytes were abundant. Lymphocytes were predominantly confined to perivascular areas, suggesting a defective migration of cells into inflamed tissue in the absence of IL-1 signaling. Impaired host defense in IL-1R(-/-) mice was further characterized by a decrease in the ability of splenocytes to produce interferon-gamma. Analysis of these data suggests that IL-1 plays an important role in the immune response to M. tuberculosis.

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IL‐12(p70), a heterodimer composed of two subunits (p35 and p40), is a key cytokine for Th1 mediated inflammatory responses. We dissected the role of IL‐12 in the development of 2,4,6‐trinitrobenzene sulfonic acid (TNBS)‐induced colitis by studying mice deficient in IL‐12p40, IL‐12p35, or IL‐12Rβ1. TNBS‐treated IL‐12Rβ1–/– and IL‐12p35–/– mice developed only a mild disease associated with low level IL‐18 expression in IL‐12p35–/– mice. In contrast, IL‐12p40–/– mice developed more severe colitis than wild‐type mice associated with high level colonic IL‐18 expression. Administration of IL‐12p40 neutralizing mononuclear antibody dramatically increased pathology in IL‐12p35–/– mice similar to disease scored in IL‐12p40–/– mice. Numbers of IFN‐γ‐producing cells infiltrating the lamina propria were comparably augmented in the different groups of IL‐12‐mutant and wild‐type mice. These results demonstrate that IL‐12p40, in contrast to IL‐12p70, inhibits TNBS‐induced colitis and IL‐18 expression independent of IFN‐γ.

Experimental data indicate that mucosal CD4+ T cells play an important role in the pathogenesis of inflammatory bowel disease (IBD). Based on the pattern of cytokine production, CD4+ T cells may be distinguished into two different phenotypes. Th1 responses are characterized by secretion of interleukin (IL)-2, tumor necrosis factor (TNF)-alpha, lymphotoxin, and interferon (IFN)-gamma and are associated with delayed-type hypersensitivity reactions, whereas Th2 responses, which are characterized by secretion of IL-4, IL-5, and IL-10, have been associated with humoral immune responses and allergy. To assess the number of IFN-alpha and IL-4 positive cells in IBD and normal intestinal specimens, frozen sections from intestinal specimens from 10 Crohn's disease (CD), 8 ulcerative colitis (UC), and 8 healthy controls were examined by immunohistochemistry. Monoclonal antibodies for CD3, CD8, IFN-gamma, and IL-4 were used. T-lymphocyte infiltration and cytokine expression by epithelial, lamina propria, and submucosal cells were scored on a four-point scale by two independent observers who were blinded for the clinical data. One-way analysis of variance (ANOVA) testing was used for statistical analysis. In intestinal specimens from IBD patients, the number of CD3+ cells was found increased in the lamina propria and, within the submucosa, this increase was significant (p < 0.001). In CD the number of lamina propria IFN-gamma positive cells was significantly increased as compared with controls (p < 0.002). In UC the number of both IFN-gamma and IL-4 producing cells in the lamina propria was not significantly increased as compared with controls. The present results confirm the existence of a Th1-biased pattern production in CD but not in UC.