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J. Biol. Chem., Vol. 280, Issue 46, 38247-38258, November 18, 2005

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Kruppel-like Factor 4 Is a Mediator of Proinflammatory Signaling in Macrophages^*

From the Program in Cardiovascular Transcriptional Biology, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115

Activation of macrophages is important in chronic inflammatory disease states such as atherosclerosis. Proinflammatory cytokines such as interferon- (IFN-), lipopolysaccharide (LPS), or tumor necrosis factor- can promote macrophage activation. Conversely, anti-inflammatory factors such as transforming growth factor-1 (TGF-1) can decrease proinflammatory 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 tumor necrosis factor- and decreased by TGF-1 in macrophages. Overexpression of KLF4 in J774a macrophages induced the macrophage activation marker inducible nitric-oxide synthase and inhibited the TGF-1 and Smad3 target gene plasminogen activator inhibitor-1 (PAI-1). Conversely, KLF4 knockdown markedly attenuated the ability of IFN-, LPS, or IFN- plus 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-B 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.

Received for publication, August 25, 2005 , and in revised form, September 9, 2005.

^* This work was supported by National Institutes of Health Grant HL-67755 (to M. W. F.), HL-69477 (to M. K. J.), HL-72952 (to M. K. J.), HL-75427 (to M. K. J.), and HL-76754 (to M. K. J.), American Heart Association Awards 0355691T (to M. W. F.) and 0250030N (to M. K. J.), and American Diabetes Association Award 1–02-JF-40 (to M. K. J.). This work was also supported by a Carl J. and Ruth Shapiro Scholar Award (to M. W. F.) and a Lerner Junior Faculty Scholar Award (to M. W. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St., Boston, MA 02115. Tel.: 617-732-7820; Fax: 617-732-5132; E-mail: mfeinberg{at}rics.bwh.harvard.edu.

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