Published online before print September 4, 2008

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(American Journal of Pathology. 2008;173:1085-1099.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.080382

Smad-Independent Transforming Growth Factor-β Regulation of Early Growth Response-1 and Sustained Expression in Fibrosis

Implications for Scleroderma

Swati Bhattacharyya^*, Shu-Jen Chen^*, Minghua Wu^*, Matthew Warner-Blankenship^*, Hongyan Ning^*, Gabriella Lakos^*, Yasuji Mori^*, Eric Chang^*, Chihiro Nihijima, Kazuhiro Takehara, Carol Feghali-Bostwick and John Varga^*

From the Division of Rheumatology,^* Northwestern University Feinberg School of Medicine, Chicago, Illinois; the Department of Dermatology, Kanazawa University, Kanazawa, Japan; and the Division of Pulmonary Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

Transforming growth factor-β (TGF-β) plays a key role in scleroderma pathogenesis. The transcription factor early growth response-1 (Egr-1) mediates the stimulation of collagen transcription elicited by TGF-β and is necessary for the development of pulmonary fibrosis in mice. Here, we report that TGF-β causes a time- and dose-dependent increase in Egr-1 protein and mRNA levels and enhanced transcription of the Egr-1 gene via serum response elements in normal fibroblasts. The ability of TGF-β to stimulate Egr-1 was preserved in Smad3-null mice and in explanted Smad3-null fibroblasts. The response was blocked by a specific mitogen-activated protein kinase kinase 1 (MEK1) inhibitor but not by an ALK5 kinase inhibitor. Furthermore, MEK1 was phosphorylated by TGF-β, which was sufficient to drive Egr-1 transactivation. Stimulation by TGF-β enhanced the transcriptional activity of Elk-1 via the MEK-extracellular signal-regulated kinase 1/2 pathway. Bleomycin-induced scleroderma in the mouse was accompanied by increased Egr-1 accumulation in lesional fibroblasts. Furthermore, biopsies of lesional skin and lung from patients with scleroderma showed increased Egr-1 levels, which were highest in early diffuse disease. Moreover, both Egr-1 mRNA and protein were elevated in explanted scleroderma skin fibroblasts in vitro. Together, these findings define a Smad-independent TGF-β signal transduction mechanism that underlies the stimulation of Egr-1, demonstrate for the first time sustained Egr-1 up-regulation in fibrotic lesions and suggests that Egr-1 has a role in the induction and progression of fibrosis.

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