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

Mei Ye, Maria E. Joosse, Ling Liu, Yu Sun, Ying Dong, Changchun Cai, Zhenmei Song, Jennifer Zhang, Steven R. Brant, Mark Lazarev, Xuhang Li

Research output: Contribution to journalArticlepeer-review

Abstract

Background and Aims: 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-/-]. Methods: 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. Results: 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. 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 signalling.

Original languageEnglish (US)
Pages (from-to)831-840
Number of pages10
JournalJournal of Crohn's and Colitis
Volume14
Issue number6
DOIs
StatePublished - Jun 1 2020

Keywords

  • Crohn's disease [CD]
  • Extraintestinal manifestation
  • Inflammatory bowel disease [IBD]
  • Interleukin 10 [IL-10]
  • Interleukin 6 [IL-6]

ASJC Scopus subject areas

  • Gastroenterology

Fingerprint Dive into the research topics of 'Deletion of IL-6 exacerbates colitis and induces systemic inflammation in IL-10-deficient mice'. Together they form a unique fingerprint.

Cite this