Glucocorticoids Modulate TGF-[beta] Production

Byline: Fu-Qiang Wen (1), Tadashi Kohyama (1), C. Magnus Skold (2), Yun Kiu Zhu (3), Xiangde Liu (1), Debra J. Romberger (1), Julie Stoner (4), Stephen I. Rennard (1) Keywords: glucocorticoids; transforming growth factor-[beta] (TGF-[beta]); Smads; AP-1 complex; fibroblast Abstract: TGF-[beta] is thought to play a central role in pulmonary fibrosis inducing fibroblast differentiation and extracellular matrix synthesis. In human lung fibroblasts, it is still unclear how various TGB-[beta] isoforms affect TGF-[beta] production and whether glucocorticoids, commonly used agents to treat fibrotic lung disease, modulate these processes. To this end, human fetal lung fibroblasts (HFL-1) were cultured with various concentrations of glucocorticoids (budesonide, dexamethasone or hydrocortisone) with and without TFG-[beta]1, -[beta]2, and -[beta]3. TGF-[beta] mRNA was assessed by real time RT-PCR. Smad 2, 3, and 4 and AP-1 complex (c-fos and c-Jun) cellular localization were evaluated by immunostaining. TGF-[beta]2 and -[beta]3 stimulated TGF-[beta]1 production significantly (p &lt 0.01 relative to control). TGF-[beta]1 stimulated TGF-[beta]2 production (p &lt 0.01 relative to control). TGF-[beta]3 was undetectable. Glucocorticoids significantly inhibited TGF-[beta]1 and -[beta]2 production and reduced expression of the upregulated TGF-[beta]1 and -[beta]2 mRNA induced by exogenous TGF-[beta]1, -[beta]2 or -[beta]3 (p &lt 0.01 for each) but had no effect on Smads. Although c-jun-related nuclear staining was not intensified in TGF-[beta]-stimulated cells, it was reduced by glucocorticoids. Thus, TGF-[beta] isoforms may stimulate production of various TGF-[beta] isoforms in the lung. Glucocorticoids then may block TGF-[beta] production by modulating mRNA levels and c-Jun. Author Affiliation: (1) Pulmonary and Critical Care Medicine Section, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska (2) Department of Medicine, Karolinska Institute, Stockholm, Sweden (3) Department of Respiratory Diseases, Jincheng Hospital, Lanzhou, China (4) Preventive and Societal Medicine Section, University of Nebraska Medical Center, Omaha, Nebraska Article History: Registration Date: 12/10/2004