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Cyclooxygenase-1 Orchestrates Germinal Center Formation and Antibody Class-Switch via Regulation of IL-17¹

Victoria A. Blaho,^* Matthew W. Buczynski, Edward A. Dennis, and Charles R. Brown^2*

^*Department of Veterinary Pathobiology and Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO 65211; and Department of Pharmacology and Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093

The cyclooxygenase (COX) enzymes are known modulators of innate immune cell function; however, their contributions to adaptive immunity are relatively unknown. We investigated the roles of COX-1 and COX-2 in the humoral immune response to infection with the Lyme disease pathogen Borrelia burgdorferi. We report that in vitro, murine B cells constitutively expressed COX-1 and up-regulated expression of both COX-1 and COX-2 as well as their products PGE₂, PGF₂, and thromboxane B₂ and their receptors following stimulation with B. burgdorferi or anti-CD40. In vitro inhibition of COX-1 and/or COX-2 in murine B cells resulted in decreased eicosanoid production and altered Ab production. Importantly, infection of mice lacking COX-1, but not COX-2, activity resulted in a defect in Ig class-switching and a lack of Borrelia-specific IgG production. This defect correlated with decreased germinal center formation and IL-6 and IL-17 production, and it could be partially recovered by restoration of IL-6, but fully recovered by IL-17. Furthermore, sera from COX-1 inhibitor-treated mice were dramatically less effective in killing B. burgdorferi, but borreliacidal activity was restored in COX-1 inhibitor-treated mice administered IL-17. We conclude that IL-17 plays a role in Ab production and Ig class-switching in response to infection and that COX-1 is a critical, previously unrecognized regulator of this response.

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 This work was supported by National Institutes of Health Grants AR052748, GM069338, a Gastroenterology Training Grant DK07202, and a University of Missouri College of Veterinary Medicine Faculty Research Award.

² Address correspondence and reprint requests to Dr. Charles R. Brown, Department of Veterinary Pathobiology, 315 Connaway Hall, University of Missouri, Columbia, MO 65211. E-mail address: brownchar{at}missouri.edu

³ Abbreviations used in this paper: GC, germinal center; COX, cyclooxygenase; tNSAID, traditional nonsteroidal antiinflammatory drug; BbAg, B. burgdorferi Ag; AA, arachidonic acid; FP, F prostanoid receptor; TP, T prostanoid receptor; TX, thromboxane; LC, liquid chromatography; MS/MS, tandem mass spectrophotometry; CLX, celecoxib; SCX, celecoxib and SC-560.