title: Essential role for Smad3 in regulating MCP-1 expression and vascular inflammation.
abstract: 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.
authors.affiliation: Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. mfeinberg@rics.bwh.harvard.edu
authors.forename: Mark W
authors.initials: MW
authors.lastname: Feinberg
authors.forename: Koichi
authors.initials: K
authors.lastname: Shimizu
authors.forename: Maria
authors.initials: M
authors.lastname: Lebedeva
authors.forename: Richard
authors.initials: R
authors.lastname: Haspel
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takayama
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Chen
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Frederick
authors.forename: Xiao-Fan
authors.initials: XF
authors.lastname: Wang
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Simon
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
authors.forename: Richard N
authors.initials: RN
authors.lastname: Mitchell
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Jain
mesh_terms: D000818:Animals; D002460:Cell Line / Q000187:drug effects; D018932:Chemokine CCL2; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D016027:Heart Transplantation; D006965:Hyperplasia; D008262:Macrophage Activation; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011183:Postoperative Complications / Q000378:metabolism / Q000473:pathology; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000502:physiology; D051900:Smad3 Protein; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000502:physiology; D014158:Transcription, Genetic; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000502:physiology; D053773:Transforming Growth Factor beta1; D014184:Transplantation, Homologous; D017539:Tunica Intima / Q000473:pathology; D014657:Vasculitis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D004268:DNA-Binding Proteins; D011506:Proteins; D011993:Recombinant Fusion Proteins; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C508961:Tgfb1 protein, mouse; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1