Deletion of IL-6 exacerbates colitis and induces systemic inflammation in IL-10-deficient mice

BACKGROUND AND AIMS: Interleukin 6 (IL-6) or its receptor is currently a candidate for targeted biologic therapy of inflammatory bowel disease (IBD). Thus, a comprehensive understanding of the consequences of blocking IL-6 is imperative. We investigated these consequences by evaluating the effects of IL-6 deletion on the spontaneous colitis of IL-10 deficient mice (IL-10-/-). METHODS: IL-6/IL-10 double-deficient mice (IL-6-/-/IL-10-/-) were generated and analyzed for intestinal inflammation, general phenotypes, and molecular/biochemical changes in the colonic mucosa by comparing to those of WT and IL-10-/- mice. RESULTS: Unexpectedly, the IL-6-/-/IL-10-/- mice manifested more pronounced gut inflammation and earlier disease onset than IL-10-/- mice, both locally (colon and small bowel) and systemically (splenomegaly, ulcerative dermatitis, leukocytosis, neutrophilia, and monocytosis). IL-6-/-/IL-10-/- mice exhibited elevations of multiple cytokines (IL-1β, IL-4, IL-12, TNFα) and chemokines (MCP-1 and MIG), but not IFN-γ (Th1), IL-17A and IL-17G (Th17), or IL-22 (Th22). FOXP3 and TGF-β, two key factors for Regulatory T (Treg) cell differentiation, were significantly down-regulated in the colonic mucosa, but not in the thymus or mesenteric lymph nodes, of IL-6-/-/IL-10-/- mice. CTLA-4 was diminished while iNOS was upregulated in the colonic mucosa of IL-6-/-/IL-10-/- mice. CONCLUSION: In IL-10-/- mice, complete IL-6 blockade significantly aggravates gut inflammation, at least in part by suppressing Treg/CTLA-4 and promoting the IL-1β/Th2 pathway. In addition, the double mutant exhibits signs of severe systemic inflammation. Our data define a new function of IL-6 and suggest that caution should be exercised when targeting IL-6 in IBD patients, particularly those with defects in IL-10 signaling.