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Papers In Press, published online ahead of print September 16, 2005
Department of Cardiology, Brigham and Women's Hospital, Boston, MA 02115
Corresponding Author: mfeinberg{at}rics.bwh.harvard.edu
Activation of macrophages is important in chronic inflammatory disease states such as atherosclerosis. Pro-inflammatory cytokines such as IFN-
J. Biol. Chem, 10.1074/jbc.M509378200
Submitted on August 25, 2005
Revised on September 9, 2005
Accepted on September 16, 2005
Kruppel-like factor 4 (KLF4) is a mediator of proinflammatory signaling in macrophages
, LPS, or TNF-
can promote macrophage activation. Conversely, anti-inflammatory factors such as TGF-
1 can decrease pro-inflammatory activation. The molecular mediators regulating the balance of these opposing effectors remain incompletely understood. Herein, we identify Kruppel-like Factor 4 (KLF4) as being markedly induced in response to IFN-, LPS, or TNF- and decreased by TGF-1 in macrophages. Overexpression of KLF4 in J774a macrophages induced the macrophage activation marker iNOS and inhibited the TGF-1 and Smad3 target gene PAI-1. Conversely, KLF4 knockdown markedly attenuated the ability of IFN-, LPS, or IFN- + LPS to induce the iNOS promoter, whereas it augmented macrophage responsiveness to TGF-1 and Smad3 signaling. The KLF4 induction of the iNOS promoter is mediated by two KLF DNA-binding sites at –95 and –212 bp and mutation of these sites diminished induction by IFN- and LPS. We further provide evidence that KLF4 interacts with the NF-kB family member, p65 (RelA), to cooperatively induce the iNOS promoter. In contrast, KLF4 inhibited the TGF-1 /Smad3 induction of the PAI-1 promoter independent of KLF4 DNA-binding through a novel antagonistic competition with Smad3 for the C-terminus of the coactivator p300/CBP. These findings support an important role for KLF4 as a regulator of key signaling pathways that control macrophage activation.
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