Transforming growth factor-β1 inhibition of macrophage activation is mediated via Smad3

Frank Werner, Mukesh K. Jain, Mark W. Feinberg, Nicholas E.S. Sibinga, Andrea Pellacani, Philippe Wiesel, Michael T. Chin, James N. Topper, Mark A. Perrella, Mu En Lee

Research output: Contribution to journalArticle

136 Scopus citations

Abstract

Activated macrophages are critical cellular participants in inflammatory disease states. Transforming growth factor (TGF)-β1 is a growth factor with pleiotropic effects including inhibition of immune cell activation. Although the pathway of gene activation by TGF-β1 via Smad proteins has recently been elucidated, suppression of gene expression by TGF-β1 remains poorly understood. We found that of Smad1-Smad7, Smad3 alone was able to inhibit expression of markers of macrophage activation (inducible nitric-oxide synthase and matrix metalloproteinase-12) following lipopolysaccharide treatment in gene reporter assays. Transient and constitutive overexpression of a dominant negative Smad3 opposed the inhibitory effect of TGF-β1. Domain swapping experiments suggest that both the Smad MH-1 and MH-2 domains are required for inhibition. Mutation of a critical amino acid residue required for DNA binding in the MH-1 of Smad3 (R74A) resulted in the loss of inhibition. Transient overexpression of p300, an interactor of the Smad MH-2 domain, partially alleviated the inhibition by TGF-β1/Smad3, suggesting that inhibition of gene expression may be due to increased competition for limiting amounts of this coactivator. Our results have implications for the understanding of gene suppression by TGF-β1 and for the regulation of activated macrophages by TGF-β1.

Original languageEnglish (US)
Pages (from-to)36653-36658
Number of pages6
JournalJournal of Biological Chemistry
Volume275
Issue number47
DOIs
StatePublished - Nov 24 2000

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Werner, F., Jain, M. K., Feinberg, M. W., Sibinga, N. E. S., Pellacani, A., Wiesel, P., Chin, M. T., Topper, J. N., Perrella, M. A., & Lee, M. E. (2000). Transforming growth factor-β1 inhibition of macrophage activation is mediated via Smad3. Journal of Biological Chemistry, 275(47), 36653-36658. https://doi.org/10.1074/jbc.M004536200