IL-7 inhibits fibroblast TGF-β production and signaling in pulmonary fibrosis

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Abstract

Based on studies by our group and others, we hypothesized that IL-7 may possess antifibrotic activities in an IFN-γ–dependent and independent manner. Here, we have evaluated the antifibrotic therapeutic potential of IL-7 in both in vitro and in vivo pulmonary fibrosis models. IL-7 inhibited both TGF-β production and signaling in fibroblasts and required an intact JAK1/STAT1 signal transduction pathway. IL-7–mediated inhibition of TGF-β signaling was found to be associated with an increase in Smad7, a major inhibitory regulator in the SMAD family. In the presence of IL-7, Smad7 dominant negative fibroblasts restored TGF-β–induced collagen synthesis, indicating that an IL-7–mediated increase in Smad7 suppressed TGF-β signaling. Consistent with these in vitro findings, recombinant IL-7 decreased bleomycin-induced pulmonary fibrosis in vivo, independent of IFN-γ. The antifibrotic activities of IL-7 merit further basic and clinical investigation for the treatment of pulmonary fibrosis.

Authors

Min Huang, Sherven Sharma, Li X. Zhu, Michael P. Keane, Jie Luo, Ling Zhang, Marie D. Burdick, Ying Q. Lin, Mariam Dohadwala, Brian Gardner, Raj K. Batra, Robert M. Strieter, Steven M. Dubinett