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Infection and Immunity, December 2001, p. 7703-7710, Vol. 69, No. 12
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.12.7703-7710.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Host Response to Infection: the Role of CpG DNA in Induction of Cyclooxygenase 2 and Nitric Oxide Synthase 2 in Murine Macrophages

Dipak K. Ghosh, Mary A. Misukonis, Charles Reich, David S. Pisetsky, and J. Brice Weinberg*

Department of Medicine, Veterans Affairs and Duke University Medical Centers, Durham, North Carolina

Received 16 May 2001/Returned for modification 24 August 2001/Accepted 13 September 2001

Depending on sequence, bacterial and synthetic DNAs can activate the host immune system and influence the host response to infection. The purpose of this study was to determine the abilities of various phosphorothioate oligonucleotides with cytosine-guanosine-containing motifs (CpG DNA) to activate macrophages to produce nitric oxide (NO) and prostaglandin E2 (PGE2) and to induce expression of NO synthase 2 (NOS2) and cyclooxygenase 2 (COX2). As little as 0.3 µg of CpG DNA/ml increased NO and PGE2 production in a dose- and time-dependent fashion in cells of the mouse macrophage cell line J774. NO and PGE2 production was noted by 4 to 8 h after initiation of cultures with the CpG DNA, with the kinetics of NO production induced by CpG DNA being comparable to that induced by a combination of lipopolysaccharide and gamma interferon. CpG DNA-treated J774 cells showed enhanced expression of NOS2 and COX2 proteins as determined by immunoblotting, with the relative potencies of the CpG DNAs generally corresponding to those noted for the induction of NO and PGE2 production as well as to those noted for the induction of interleukin-6 (IL-6), IL-12, and tumor necrosis factor. Extracts from CpG DNA-treated cells converted L-arginine to L-citrulline, but the NOS inhibitor NG-monomethyl-L-arginine (NMMA) inhibited this reaction. The COX2-specific inhibitor NS398 inhibited CpG DNA-induced PGE2 production and inhibited NO production to various degrees. The NOS inhibitors NMMA, 1400W, and N-iminoethyl-L-lysine effectively blocked NO production and increased the production of PGE2 in a dose-dependent fashion. Thus, analogues of microbial DNA (i.e., CpG DNA) activate mouse macrophage lineage cells for the expression of NOS2 and COX2, with the production of NO and that of PGE2 occurring in an interdependent manner.

* Corresponding author. Mailing address: VA and Duke University Medical Centers, 508 Fulton St., Durham, NC 27705. Phone: (919) 286-6833. Fax: (919) 296-6891. E-mail: brice{at}acpub.duke.edu.

Infection and Immunity, December 2001, p. 7703-7710, Vol. 69, No. 12
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.12.7703-7710.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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