Cytokines mediating the induction of chronic colitis and colitis-associated fibrosis.
To investigate the immunopathogenesis of inflammation-associated fibrosis we analyzed the chronic colitis and late-developing fibrosis occurring in BALB/c mice administered weekly doses of intrarectal trinitrobenzene sulfonic acid (TNBS). We showed first in this model that an initial T helper type 1 response involving interleukin (IL)-12p70 and interferon-gamma subsides after 3 weeks to be supplanted by an IL-23/IL-25 response beginning after 4-5 weeks. This evolution is followed by gradually increasing production of IL-17 and cytokines ordinarily seen in a T helper type 2 response, particularly IL-13, which reaches a plateau at 8-9 weeks. We then show that IL-13 production results in the induction of an IL-13 receptor formerly thought to function only as a decoy receptor, IL-13Ralpha(2), and this receptor is critical to the production of tumor growth factor (TGF)-beta(1) and the onset of fibrosis. Thus, if IL-13 signaling through this receptor is blocked by administration of soluble IL-13Ralpha(2)-Fc, or by administration of IL-13Ralpha(2)-specific siRNA, TGF-beta(1) is not produced and fibrosis does not occur. These studies show that in chronic TNBS colitis, fibrosis is dependent on the development of an IL-13 response that acts through a novel cell-surface-expressed IL-13 receptor to induce TGF-beta(1).
Fichtner-Feigl
S
S
Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. stefan.fichtner@klinik.uni-regensburg.de
Strober
W
W
Geissler
E K
EK
Schlitt
H-J
HJ
D000818:Animals; D002908:Chronic Disease; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D005355:Fibrosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics
D016207:Cytokines; D003094:Collagen