Deletion of IL-6 Exacerbates Colitis and Induces Systemic Inflammation in IL-10-Deficient Mice

Abstract

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background and Aims</jats:title> <jats:p>Interleukin 6 [IL-6] or its receptor is currently a candidate for targeted biological therapy of inflammatory bowel disease [IBD]. Thus, a comprehensive understanding of the consequences of blocking IL-6 is imperative. We investigated this by evaluating the effects of IL-6 deletion on the spontaneous colitis of IL-10-deficient mice [IL-10−/−].</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>IL-6/IL-10 double-deficient mice [IL-6−/−/IL-10−/−] were generated and analysed for intestinal inflammation, general phenotypes and molecular/biochemical changes in the colonic mucosa compared with wild-type and IL-10−/− mice.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>Unexpectedly, the IL-6−/−/IL-10−/− mice showed 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 up-regulated in the colonic mucosa of IL-6−/−/IL-10−/− mice.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion</jats:title> <jats:p>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 signalling.</jats:p> </jats:sec>

Pancreastatin Reduces Alternatively Activated Macrophages, Disrupts the Epithelial Homeostasis and Aggravates Colonic Inflammation. A Descriptive Analysis

“…This is an important feature, especially in the role portrayed by AAM in restraining the excessive inflammatory immune response and promoting tissue repair [ 5 ]. Several studies support our findings, demonstrating that mice with a deficient AAM polarization expressed higher susceptibility to colitis [ 6 , 45 , 46 ]. This is in accordance with the notion that polarized AAM drives a directionally concordant expansion of regulatory T cells to establish mucosal tolerance and protect against colitis [ 44 ].…”

Bioinformatics Analysis of Differentially Expressed Genes and Protein–Protein Interaction Networks Associated with Functional Pathways in Ulcerative Colitis

“…IL-10 plays an important role in UC. Previous studies [ 12 , 16 ] revealed that intestinal inflammation may be aggravated in individuals with IL-10 deficiency through inhibition of regulatory T cells/cytotoxic T-lymphocyte-associated protein 4 and through promotion of the IL-1β/T helper 2 cell pathway. Studies have shown that IL-10 can negatively regulate CXCL8 , CXCL1 , IL-1 β, CCL20 , and PTGS2 [ 17 – 19 ].…”

Epac‐2 ameliorates spontaneous colitis in Il‐10−/− mice by protecting the intestinal barrier and suppressing NF‐κB/MAPK signalling

“…The Il ‐ 10 −/− model is the closest animal model to the CD phenotype. 21 We investigated the clinical results and effective mechanisms of Epac‐2 in Il ‐ 10 −/− mice treated with Me‐cAMP (an Epac‐2 agonist) or HJC‐0350 (an Epac‐2 antagonist). Colonic expression of Epac‐2 was abnormal in CD patients, and Epac‐2 activated the Rap‐1 pathway and inhibited the phosphorylation of NF‐κB/MAPK in macrophages, which increased the levels of ZO‐1 and occludin in intestinal epithelial cells.…”