Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, Non-P.H.S.
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Animals
-
Bleomycin / adverse effects
-
Cells, Cultured
-
Collagen / biosynthesis
-
DNA-Binding Proteins / genetics
-
DNA-Binding Proteins / immunology
-
Female
-
Fibroblasts / cytology
-
Fibroblasts / drug effects
-
Fibroblasts / immunology
-
Gene Expression
-
Humans
-
Interleukin-7 / immunology*
-
Interleukin-7 / pharmacology
-
Janus Kinase 1
-
Mice
-
Mice, Inbred C57BL
-
Mice, SCID
-
Protein-Tyrosine Kinases / immunology
-
Pulmonary Fibrosis / immunology*
-
Recombinant Proteins / immunology
-
Recombinant Proteins / pharmacology
-
STAT1 Transcription Factor
-
Signal Transduction / immunology*
-
Smad7 Protein
-
Trans-Activators / genetics
-
Trans-Activators / immunology
-
Transforming Growth Factor beta / biosynthesis*
-
Transforming Growth Factor beta1
-
Transforming Growth Factor beta2
-
Transforming Growth Factor beta3
Substances
-
DNA-Binding Proteins
-
Interleukin-7
-
Recombinant Proteins
-
SMAD7 protein, human
-
STAT1 Transcription Factor
-
STAT1 protein, human
-
Smad7 Protein
-
Smad7 protein, mouse
-
Stat1 protein, mouse
-
TGFB1 protein, human
-
TGFB2 protein, human
-
Tgfb1 protein, mouse
-
Tgfb3 protein, mouse
-
Trans-Activators
-
Transforming Growth Factor beta
-
Transforming Growth Factor beta1
-
Transforming Growth Factor beta2
-
Transforming Growth Factor beta3
-
Bleomycin
-
Collagen
-
Protein-Tyrosine Kinases
-
JAK1 protein, human
-
Jak1 protein, mouse
-
Janus Kinase 1