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Sci. STKE, 22 May 2007
Vol. 2007, Issue 387, p. tw174
[DOI: 10.1126/stke.3872007tw174]

EDITORS' CHOICE

Lung Fibrosis TGF-beta1 Uses Semaphorin

John F. Foley

Science’s STKE, AAAS, Washington, DC 20005, USA

The transforming growth factor beta (TGF-beta) family of cytokines perform many important functions in processes such as inflammation, cell growth, and tissue remodeling, to name but a few. TGF-beta1 is essential for wound healing and has been implicated in the pathogenesis of fibrotic disorders, such as idiopathic pulmonary fibrosis. The semaphorins are another large family of proteins, members of which are known to be critical for axon guidance and have been implicated in pathologies such as Alzheimer’s disease. Kang et al. investigated a possible role for the semaphorin SEMA7A in contributing to TGF-beta1-induced fibrosis in the lung. They established two transgenic mouse strains with doxycycline-inducible expression of TGF-beta1, one of which was also a SEMA7A-deficient mouse (SEMA7A KO), whereas the other TGF-beta1 transgenic animal was wild type (WT) with respect to SEMA7A. In this way the authors could investigate the effects of overproduction of TGF-beta1 (through the administration of doxycycline-water to mice) in the presence or absence of SEMA7A. Real-time reverse transcription polymerase chain reaction (RT-PCR) and Western blotting analyses showed that TGF-beta1 stimulated an increase in the production of SEMA7A and its receptors, plexin C1 and integrin beta1. TGF-beta1 caused fibrosis in the lungs of WT mice, as shown by histological analysis, but this was much reduced in SEMA7A KO mice. The collagen content of the lungs of wild-type mice was much higher than that in the lungs of SEMA7A KO mice, further demonstrating a role for SEMA 7A in mediating the fibrotic effects of TGF-beta1. Loss of SEMA7A did not adversely affect the ability of TGF-beta1 to activate its target transcription factors Smads 2 and 3, indicating that SEMA7A did not have a role in mediating TGF-beta1-induced inflammation. The ability of TGF-beta1 to stimulate the production of extracellular matrix-associated proteins such as collagens, elastin, and fibronectin, and fibroregulatory cytokines including IL-18, was completely abolished in the absence of SEMA7A. Deletion of SEMA7A also blocked the ability of TGF-beta1 to activate phosphatidylinositol 3-kinase and protein kinase B. Finally, bleomycin-induced fibrosis (which is dependent on TGF-beta1) was greatly diminished in SEMA7A KO mice compared with WT mice, as measured by histochemistry and collagen content. This study provides evidence for a previously unappreciated role for SEMA7A in meditating the effects of TGF-beta1 in tissue fibrosis.

H.-R. Kang, C. G. Lee, R. J. Homer, J. A. Elias, Semaphorin 7A plays a critical role in TGF-beta1-induced pulmonary fibrosis. J. Exp. Med. 204, 1083-1093 (2007). [Abstract] [Full Text]

Citation: J. F. Foley, TGF-beta1 Uses Semaphorin. Sci. STKE 2007, tw174 (2007).


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