Essential role for Smad3 in regulating MCP-1 expression and vascular inflammation.

Published

Journal Article

Transforming growth factor (TGF)-beta(1) is a pleiotropic growth factor with known inhibitory effects on immune cell activation. However, the specific mechanism(s) and in vivo significance of the effectors of TGF-beta(1) modulation in the context of vascular inflammation are not well characterized. The chemokine monocyte chemoattractant protein (MCP)-1 is critical for the recruitment of macrophages in inflammatory disease states. In this study, we provide definitive evidence that the ability of TGF-beta(1) to inhibit MCP-1 expression is mediated via its effector Smad3. Adenoviral overexpression of Smad3 potently repressed inducible expression of endogenous MCP-1. Conversely, TGF-beta(1) inhibition of cytokine-mediated induction of MCP-1 expression was completely blocked in Smad3-deficient macrophages. Consistent with this impaired response, cardiac allografts in Smad3-deficient mice developed accelerated intimal hyperplasia with increased infiltration of adventitial macrophages expressing MCP-1. Previous studies show that MCP-1 inducibility is regulated by an AP-1 complex composed of c-Jun/c-Fos heterodimers. We demonstrate that the inhibitory effect of Smad3 occurs via a novel antagonistic effect of Smad3 on AP-1 DNA-protein binding and activity. Thus, Smad3 plays an essential role in modulating vascular inflammation characteristic of transplant-associated arteriopathy, is important in regulating MCP-1 expression, and plays a critical role in the ability of TGF-beta(1) to repress stimuli from a major inflammatory signaling pathway.

Full Text

Duke Authors

Cited Authors

  • Feinberg, MW; Shimizu, K; Lebedeva, M; Haspel, R; Takayama, K; Chen, Z; Frederick, JP; Wang, X-F; Simon, DI; Libby, P; Mitchell, RN; Jain, MK

Published Date

  • March 19, 2004

Published In

Volume / Issue

  • 94 / 5

Start / End Page

  • 601 - 608

PubMed ID

  • 14752027

Pubmed Central ID

  • 14752027

Electronic International Standard Serial Number (EISSN)

  • 1524-4571

Digital Object Identifier (DOI)

  • 10.1161/01.RES.0000119170.70818.4F

Language

  • eng

Conference Location

  • United States