Induction of IL-13 triggers TGF-beta1-dependent tissue fibrosis in chronic 2,4,6-trinitrobenzene sulfonic acid colitis.
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 2,4,6-trinitrobenzene sulfonic acid. We showed first in this model that an initial Th1 response involving IL-12p70 and IFN-gamma subsides after 3 wk to be supplanted by an IL-23/IL-25 response beginning after 4-5 wk. This evolution is followed by gradually increasing production of IL-17 and cytokines ordinarily seen in a Th2 response, particularly IL-13, which reaches a plateau at 8-9 wk. In vitro stimulation studies suggest that this IL-13 production is dependent on IL-23 and IL-25, but not on IL-12p70. We then show that IL-13 production results in the induction of an IL-13R formerly thought to function only as a decoy receptor, IL-13Ralpha(2), and this receptor is critical to the production of 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 small interfering RNA, TGF-beta(1) is not produced and fibrosis does not occur. These studies show that in chronic 2,4,6-trinitrobenzene sulfonic acid colitis, fibrosis is dependent on the development of an IL-13 response that acts through a novel cell surface-expressed IL-13R to induce TGF-beta(1). A similar mechanism may obtain in certain forms of human inflammatory bowel disease.
Fichtner-Feigl
Stefan
S
Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. stefan.fichtner@klinik.uni-regensburg.de
Fuss
Ivan J
IJ
Young
Cheryl A
CA
Watanabe
Tomohiro
T
Geissler
Edward K
EK
Schlitt
Hans-Jürgen
HJ
Kitani
Atsushi
A
Strober
Warren
W
D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology*; D005355:Fibrosis; D007371:Interferon-gamma / Q000378:metabolism; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism*; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000494:pharmacology; D053660:Receptors, Interleukin-13 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism; D051906:Smad7 Protein / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity
D018793:Interleukin-13; D053663:Interleukin-13 Receptor alpha2 Subunit; D007378:Interleukins; D034741:RNA, Small Interfering; D053660:Receptors, Interleukin-13; D051900:Smad3 Protein; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D053773:Transforming Growth Factor beta1; D007371:Interferon-gamma; D014302:Trinitrobenzenesulfonic Acid