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J. Biol. Chem., Vol. 280, Issue 7, 5491-5495, February 18, 2005

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Transforming Growth Factor- Differentially Inhibits MyD88-dependent, but Not TRAM- and TRIF-dependent, Lipopolysaccharide-induced TLR4 Signaling^*

Yoshikazu Naiki, Kathrin S. Michelsen, Wenxuang Zhang, Shuang Chen, Terence M. Doherty, and Moshe Arditi¶

From the Department of Pediatric Infectious Diseases, Division of Cardiology, Atherosclerosis Research Center, Cedars-Sinai Medical Center, Burns and Allen Research Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90048

Transforming growth factor-1 (TGF-1) is a multifunctional, potent anti-inflammatory cytokine produced by many cell types that regulates cell proliferation, apoptosis, and immune responses. Toll-like receptors (TLRs) recognize various pathogen-associated molecular patterns and are therefore a pivotal component of the innate immune system. In this study we show that TGF-1 blocks the NF-B activation and cytokine release that is stimulated by ligands for TLRs 2, 4, and 5. We further show that TGF-1 can specifically interfere with TLR2, -4, or -5 ligand-induced responses involving the adaptor molecule MyD88 (myeloid differentiation factor 88) but not the TRAM/TRIF signaling pathway by decreasing MyD88 protein levels in a dose- and time-dependent manner without altering its mRNA expression. The proteasome inhibitor epoxomicin abolished the MyD88 degradation induced by TGF-1. Furthermore, TGF-1 resulted in ubiquitination of MyD88 protein, suggesting that TGF-1 facilitates ubiquitination and proteasomal degradation of MyD88 and thereby attenuates MyD88-dependent signaling by decreasing cellular levels of MyD88 protein. These findings importantly contribute to our understanding of molecular mechanisms mediating anti-inflammatory modulation of immune responses by TGF-1.

Received for publication, October 25, 2004 , and in revised form, December 23, 2004.

^* This work was supported by National Institutes of Health Grants HL 66436 and AI 058128 (to M. A.). 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.

^¶ To whom correspondence and reprint requests should be addressed: Dept. of Pediatric Infectious Diseases, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Rm. 4220, Los Angeles, CA 90048. Tel.: 310-423-4064; Fax: 310-423-8284; E-mail: moshe.arditi{at}cshs.org.

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