Transforming growth factor-βl induces macrophage-colony stimulating factor via a signaling pathway involving a flavinlinked oxidase and h,o

Academic Article


  • Transforming growth factor βl (TGF-βl) exerts diverse effects on vascular wall cells, but its role in regulating proinflammatory cytokines is not known. Here we show that TGF-βl induces the expression of macrophage-colony stimulating factor (M-CSF) in vascular endothelial cells via signalling pathway(s) requiring the generation of H22O2. In a time-dependent manner, TGF-βl stimulated extracellular release of H22OZ, NF-B activation, and M-CSF steady-state mRNA levels. These effects of TGF-B1 were attenuated in the presence of the flavin inhibitor, diphenylene iodonium (DPI), and the NAD(P)H inhibitor, apocynin. The induction of M-CSF expression by TGF-βl was augmented by NADH but not by NADPH, and not by Superoxide dismutase (SOD) or cGMP analogues. Transfection assays using M-CSF promoter constructs linked to the chloramphemcol acetyttransferase reporter gene demonstrated that DPI, NO, and calalase attenuated M-CSF gene transcription, in part, through their inhibitory effects on nuclear factor-kappa B (NF-/cB). Electrophoretic mobility shift assay showed that activation of NF-B by TGF-βl was similarly inhibited by DPI, NO, and catalase, but not by SOD, suggesting that HzOj rather than Superoxide anion (O2 ') mediates NF-B activation. These results indicate that the production of H-4 by a flavin-linked oxidase may mediate some of TGF-βl's proinflammatory effects.
  • Published In

    Pubmed Id

  • 14657628
  • Author List

  • Thannickal VJ; Hong YH; Peng HB; Fanburg BL; Liao JK
  • Volume

  • 44
  • Issue

  • 3