IL-13 activates a mechanism of tissue fibrosis that is completely TGF-beta independent.
Fibrosis is a characteristic feature in the pathogenesis of a wide spectrum of diseases. Recently, it was suggested that IL-13-dependent fibrosis develops through a TGF-beta1 and matrix metalloproteinase-9-dependent (MMP-9) mechanism. However, the significance of this pathway in a natural disorder of fibrosis was not investigated. In this study, we examined the role of TGF-beta in IL-13-dependent liver fibrosis caused by Schistosoma mansoni infection. Infected IL-13-/- mice showed an almost complete abrogation of fibrosis despite continued and undiminished production of TGF-beta1. Although MMP-9 activity was implicated in the IL-13 pathway, MMP-9-/- mice displayed no reduction in fibrosis, even when chronically infected. To directly test the requirement for TGF-beta, studies were also performed with neutralizing anti-TGF-beta Abs, soluble antagonists (soluble TGF-betaR-Fc), and Tg mice (Smad3-/- and TGF-betaRII-Fc Tg) that have disruptions in all or part of the TGF-beta signaling cascade. In all cases, fibrosis developed normally and with kinetics similar to wild-type mice. Production of IL-13 was also unaffected. Finally, several genes, including interstitial collagens, several MMPs, and tissue inhibitors of metalloprotease-1 were up-regulated in TGF-beta1-/- mice by IL-13, demonstrating that IL-13 activates the fibrogenic machinery directly. Together, these studies provide unequivocal evidence of a pathway of fibrogenesis that is IL-13 dependent but TGF-beta1 independent, illustrating the importance of targeting IL-13 directly in the treatment of infection-induced fibrosis.
Kaviratne
Mallika
M
Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Hesse
Matthias
M
Leusink
Mary
M
Cheever
Allen W
AW
Davies
Stephen J
SJ
McKerrow
James H
JH
Wakefield
Lalage M
LM
Letterio
John J
JJ
Wynn
Thomas A
TA
D000818:Animals; D002478:Cells, Cultured; D002908:Chronic Disease; D004268:DNA-Binding Proteins / Q000502:physiology; D005109:Extracellular Matrix / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005260:Female; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000276:immunology; D018793:Interleukin-13 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008099:Liver / Q000201:enzymology / Q000276:immunology / Q000469:parasitology / Q000473:pathology*; D008103:Liver Cirrhosis / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000469:parasitology; D020780:Matrix Metalloproteinase 9 / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012555:Schistosomiasis mansoni / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051900:Smad3 Protein; D015534:Trans-Activators / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D053773:Transforming Growth Factor beta1; D014945:Wound Healing / Q000235:genetics / Q000276:immunology
D004268:DNA-Binding Proteins; D018793:Interleukin-13; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C508961:Tgfb1 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D020780:Matrix Metalloproteinase 9