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J. Biol. Chem., Vol. 283, Issue 40, 26850-26858, October 3, 2008

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Suppression of Lipopolysaccharide-stimulated Tumor Necrosis Factor- Production by Adiponectin Is Mediated by Transcriptional and Post-transcriptional Mechanisms^*

Pil-Hoon Park¹, Honglian Huang¹, Megan R. McMullen¹, Palash Mandal, Lei Sun, and Laura E. Nagy²

From the Departments of Pathobiology and Gastroenterology, Cleveland Clinic, Cleveland, Ohio 44195

Adiponectin is an adipokine with potent anti-inflammatory properties. Treatment of macrophages with adiponectin results in a suppression of lipopolysaccharide (LPS)-stimulated cytokine production. Here we investigated the transcriptional and post-transcriptional mechanisms by which adiponectin suppresses LPS-stimulated tumor necrosis factor (TNF)- production. Treatment of RAW 264.7 macrophages with LPS increased TNF- promoter-driven luciferase activity (TNF- promoter/Luc activity) by 20-fold over basal. After culture with 1 µg/ml globular adiponectin (gAcrp) for 18 h, TNF- promoter/Luc activity was increased even in the absence of LPS; further challenge with LPS only increased TNF- promoter/Luc activity by 1.4-fold. Treatment with gAcrp decreased LPS-stimulated ERK1/2 phosphorylation and IB degradation and suppressed the ability of LPS to increase the DNA binding activity of Egr-1 and p65. gAcrp also suppressed LPS-mediated stabilization of TNF- mRNA. In controls cells, the half-life of TNF- mRNA was increased from 30 min at base line to 80 min in response to LPS. After treatment with gAcrp for 18 h, LPS failed to increase TNF- mRNA stability. This gAcrp-mediated loss of stimulus-induced stabilization of TNF- mRNA required the presence of the TNF- 3'-untranslated region and was associated with an increase in expression and RNA binding activity of tristetraprolin, an mRNA-binding protein that destabilizes TNF- mRNA. In summary, these data characterize the complex transcriptional and post-transcriptional effects of gAcrp on LPS-stimulated TNF- expression in macrophages. gAcrp treatment profoundly suppressed the ability of LPS to increase TNF- transcription and reduced the stimulus-induced stabilization of TNF- mRNA in response to LPS.

Received for publication, April 10, 2008 , and in revised form, July 8, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants AA011975 and AA013868 (to L. E. N.). 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 Both authors contributed equally to this work.

² To whom correspondence should be addressed: Cleveland Clinic Foundation, LRI/NE40, 9500 Euclid Ave., Cleveland, OH 44195. Tel.: 216-444-4021; Fax: 216-636-1493; E-mail: laura.nagy{at}case.edu.

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