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Accelerated fibrosis in the combined absence of Interleukin‐13 regulatory molecules: IL‐13 receptor alpha 2, IL‐10 and IL‐12
Author(s) -
MentinkKane Margaret M,
Wynn Thomas A,
Cheever Allen
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.2_supplement.412
Subject(s) - fibrosis , immunology , immune system , cytokine , interleukin 13 , schistosoma mansoni , medicine , pulmonary fibrosis , interleukin , hepatic fibrosis , biology , cancer research , pathology , schistosomiasis , helminths
Tissue fibrosis contributes to the morbidity of a variety of diseases and can affect many organs including heart, lung and liver. The development of anti‐fibrotic therapies to inhibit and/or reverse fibrosis has focused on immune modulators that suppress collagen synthesis. We sought to identify endogenous mechanisms regulating IL‐13, the primary Th2 cytokine that drives liver fibrosis during infection with the parasite Schistosoma mansoni . Previous studies showed that IL‐10 and IL‐12 modulated the inflammatory response following S.mansoni infection and that IL‐13 effects were tightly regulated by the decoy activity of IL‐13Rα2. Furthermore, mice deficient in IL‐13Rα2 had exacerbated fibrosis when examined at acute infection (WK8) and compared to control mice. We generated mice with targeted deletions of IL‐10, IL‐12 and IL‐13Rα2 to characterize the development of liver fibrosis in the combined absence of these critical Th2 attenuators. The IL‐10/12/13Rα2 −/− mice developed severe liver fibrosis and succumbed to acute infection (>95% mortality) by WK10. However, anti‐IL‐13 Ab treatment not only significantly reduced liver fibrosis but rescued mice from death. Our studies suggest that the rapid and unchecked tissue fibrosis in these unique IL‐10/12/13Rα2 −/− mice may prove a useful read‐out for models examining IL‐13 effector responses in fibrosis, angiogenesis and cancer immunology.