IL-7 inhibits fibroblast TGF-beta production and signaling in pulmonary fibrosis.
Based on studies by our group and others, we hypothesized that IL-7 may possess antifibrotic activities in an IFN-gamma-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-beta production and signaling in fibroblasts and required an intact JAK1/STAT1 signal transduction pathway. IL-7-mediated inhibition of TGF-beta 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-beta-induced collagen synthesis, indicating that an IL-7-mediated increase in Smad7 suppressed TGF-beta signaling. Consistent with these in vitro findings, recombinant IL-7 decreased bleomycin-induced pulmonary fibrosis in vivo, independent of IFN-gamma. The antifibrotic activities of IL-7 merit further basic and clinical investigation for the treatment of pulmonary fibrosis.
Huang
Min
M
Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of California Los Angeles School of Medicine, Los Angeles, California 90095-1690, USA.
Sharma
Sherven
S
Zhu
Li X
LX
Keane
Michael P
MP
Luo
Jie
J
Zhang
Ling
L
Burdick
Marie D
MD
Lin
Ying Q
YQ
Dohadwala
Mariam
M
Gardner
Brian
B
Batra
Raj K
RK
Strieter
Robert M
RM
Dubinett
Steven M
SM
D000818:Animals; D001761:Bleomycin / Q000009:adverse effects; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D015870:Gene Expression; D006801:Humans; D015851:Interleukin-7 / Q000276:immunology* / Q000494:pharmacology; D053613:Janus Kinase 1; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D011505:Protein-Tyrosine Kinases / Q000276:immunology; D011658:Pulmonary Fibrosis / Q000276:immunology*; D011994:Recombinant Proteins / Q000276:immunology / Q000494:pharmacology; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000276:immunology*; D051906:Smad7 Protein; D015534:Trans-Activators / Q000235:genetics / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis*; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D053782:Transforming Growth Factor beta3
D004268:DNA-Binding Proteins; D015851:Interleukin-7; D011994:Recombinant Proteins; C497806:SMAD7 protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; C494080:Stat1 protein, mouse; C508960:TGFB1 protein, human; C509041:TGFB2 protein, human; C508961:Tgfb1 protein, mouse; C509045:Tgfb3 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D053782:Transforming Growth Factor beta3; D001761:Bleomycin; D003094:Collagen; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1