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J. Biol. Chem., Vol. 278, Issue 42, 40590-40600, October 17, 2003

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Myeloid Differentiation Factor 88-dependent Post-transcriptional Regulation of Cyclooxygenase-2 Expression by CpG DNA

TUMOR NECROSIS FACTOR- RECEPTOR-ASSOCIATED FACTOR 6, A DIVERGING POINT IN THE Toll-LIKE RECEPTOR 9-SIGNALING^*

Seon-Ju Yeo  , Jae-Geun Yoon  and Ae-Kyung Yi  ¶ ||

From the Children's Foundation Research Center at Le Bonheur Children's Medical Center, Department of Pediatrics and the ^¶Department of Molecular Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38103

The immune stimulatory unmethylated CpG motifs present in bacterial DNA (CpG DNA) induce expression of cyclooxygenase-2 (cox-2). The present study demonstrates that CpG DNA can up-regulate cox-2 expression by post-transcriptional mechanisms in RAW264.7 cells. To determine the CpG DNA-mediated signaling pathway that post-transcriptionally regulates cox-2 expression, a cox-2 translational reporter (COX2–3'-UTR-luciferase) was generated by inserting sequences within the 3'-untranslated region (UTR) of cox-2 to the 3' end of the luciferase gene under control of the SV40 promoter. CpG DNA-induced COX2–3'-UTR-luciferase activity was completely inhibited by an endosomal acidification inhibitor chloroquine, a Toll-like receptor 9 antagonist inhibitory CpG DNA, or overexpression of a dominant negative (DN) form of MyD88. However, overexpression of DN-IRAK-1 or DN-TRAF6 resulted in substantial, but not complete, inhibition of the CpG DNA-induced COX2–3'-UTR-luciferase activity. Activation of all three MAPKs (ERK, p38, and JNK) was required for optimal COX2–3'-UTR-luciferase activity induced by CpG DNA. Overexpression of DN-TRAF6 suppressed CpG DNA-mediated activation of p38 and JNK, but not ERK, explaining the partial inhibitory effects of DN-TRAF6 on CpG DNA-induced COX2–3'-UTR-luciferase activity. Co-expression of DN-TRAF6 and N17Ras completely inhibited CpG DNA-induced COX2–3'-UTR-luciferase activity, indicating the involvement of Ras in CpG DNA-mediated ERK and COX2–3'-UTR regulation. Collectively, our results suggest that MyD88 and MAPKs play a key regulatory role in CpG DNA-mediated cox-2 expression at the post-transcriptional level and that TRAF6 is a diverging point in the Toll-like receptor 9-signaling pathway for CpG DNA-mediated MAPK activation.

Received for publication, June 13, 2003 , and in revised form, August 4, 2003.

^* 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.

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

^|| Supported by Children's Foundation Research Center at Le Bonheur Children's Medical Center, Vascular Biology Center of Excellence, Center of Excellence for Diseases of Connective Tissue, and Rheumatic Disease Research Core Center, United States Public Health Service Grant AR-47379 at the University of Tennessee, National Institutes of Health Grant 1R03AR47757, and the Leukemia Research Foundation. To whom correspondence should be addressed: Children's Foundation Research Center, Department of Pediatrics, University of Tennessee Health Science Center, 50 N. Dunlap St., WPT 315, Memphis, TN 38103. Tel.: 901-572-4475; Fax: 901-572-5036; E-mail: ayi{at}utmem.edu.

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