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J. Biol. Chem., Vol. 283, Issue 22, 15258-15270, May 30, 2008

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CpG DNA Prevents Liver Injury and Shock-mediated Death by Modulating Expression of Interleukin-1 Receptor-associated Kinases^*

Young-In Kim¹, Jeoung-Eun Park², Antonio Martinez-Hernandez^¶, and Ae-Kyung Yi^||3

From the The Children's Foundation Research Center at Le Bonheur Children's Medical Center and the Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee 38103, the Department of Pathology and Laboratory Medicine and ^||Department of Molecular Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163, and ^¶Pathology and Laboratory Medicine Service, Veteran Affairs Medical Center, Memphis, Tennessee 38104

Tumor necrosis factor- (TNF-) produced by macrophages in response to CpG DNA induces severe liver injury and subsequent death of D-galactosamine (D-GalN)-sensitized mice. In the present study we demonstrate that mice pre-exposed to CpG DNA are resistant to liver injury and death induced by CpG DNA/D-GalN. CpG DNA/D-GalN failed to induce TNF- production and hepatocyte apoptosis in the mice pre-exposed to CpG DNA. In addition, macrophages isolated from the CpG DNA-pretreated mice showed suppressed activation of MAPKs and NF-B and production of TNF- in response to CpG DNA, indicating that the CpG DNA-mediated protection of CpG DNA/D-GalN-challenged mice is due to the hyporesponsiveness of macrophages to CpG DNA. CpG DNA pretreatment in vivo inhibited expression of interleukin-1 receptor-associated kinase (IRAK)-1 while inducing IRAK-M expression in macrophages. Suppressed expression of IRAK-1 was responsible for the macrophage hyporesponsiveness to CpG DNA. However, increased expression of IRAK-M was not sufficient to render macrophages hyporesponsive to CpG DNA but was required for induction of the optimal level of macrophage hyporesponsiveness. Taken together, reduced expression of IRAK-1 and increased expression of IRAK-M after CpG DNA pretreatment resulted in the hyporesponsiveness of macrophages that leads to the protection of mice from hepatic injury and death caused by CpG DNA/D-GalN.

Received for publication, November 21, 2007 , and in revised form, February 7, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant AI053137 (to A.-K. Y.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table 1 and Figs. 1–6.

¹ Supported by a postdoctoral fellowship from the Korea Research Foundation (KRF-2005-214-E00045) and a grant from Le Bonheur Children's Medical Center.

² Supported by a grant from Le Bonheur Children's Medical Center.

³ Supported by grants from the Musette and Allen Morgan, Jr. Foundation^M for the Study of Primary Sclerosing Cholangitis and by the Children's^M Foundation of Memphis

³ To whom correspondence should be addressed: Dept. of Pediatrics, University of Tennessee Health Science Center, 50 N. Dunlap St., Rm. 315 WPT, Memphis, TN 38103. Tel.: 901-287-4475; Fax: 901-287-5036; E-mail: ayi{at}utmem.edu.

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