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.
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 IBDpatients, particularly those with defects in IL-10 signalling.
Authors: Estelle Bettelli; Yijun Carrier; Wenda Gao; Thomas Korn; Terry B Strom; Mohamed Oukka; Howard L Weiner; Vijay K Kuchroo Journal: Nature Date: 2006-04-30 Impact factor: 49.962
Authors: I I Singer; D W Kawka; S Scott; J R Weidner; R A Mumford; T E Riehl; W F Stenson Journal: Gastroenterology Date: 1996-10 Impact factor: 22.682
Authors: S E Erdman; V P Rao; T Poutahidis; A B Rogers; C L Taylor; E A Jackson; Z Ge; C W Lee; D B Schauer; G N Wogan; S R Tannenbaum; J G Fox Journal: Proc Natl Acad Sci U S A Date: 2009-01-21 Impact factor: 11.205
Authors: Ling Liu; Ying Dong; Mei Ye; Shi Jin; Jianbo Yang; Maria E Joosse; Yu Sun; Jennifer Zhang; Mark Lazarev; Steven R Brant; Bashar Safar; Michael Marohn; Esteban Mezey; Xuhang Li Journal: J Crohns Colitis Date: 2017-06-01 Impact factor: 9.071
Authors: Nick Powell; Jonathan W Lo; Paolo Biancheri; Anna Vossenkämper; Eirini Pantazi; Alan W Walker; Emilie Stolarczyk; Francesca Ammoscato; Rimma Goldberg; Paul Scott; James B Canavan; Esperanza Perucha; Natividad Garrido-Mesa; Peter M Irving; Jeremy D Sanderson; Bu Hayee; Jane K Howard; Julian Parkhill; Thomas T MacDonald; Graham M Lord Journal: Gastroenterology Date: 2015-04-25 Impact factor: 22.682
Authors: Paolo Giuffrida; Sara Cococcia; Mariangela Delliponti; Marco Vincenzo Lenti; Antonio Di Sabatino Journal: Cells Date: 2019-04-30 Impact factor: 6.600
Authors: Balaji Venkataraman; Saeeda Almarzooqi; Vishnu Raj; Abdullah T Alhassani; Ahmad S Alhassani; Khadijah J Ahmed; Veedamali S Subramanian; Shreesh K Ojha; Samir Attoub; Thomas E Adrian; Sandeep B Subramanya Journal: Nutrients Date: 2021-04-17 Impact factor: 5.717