Cyclooxygenase-1 orchestrates germinal center formation and antibody class-switch via regulation of IL-17.
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 PGE(2), PGF(2alpha), and thromboxane B(2) 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.
Department of Veterinary Pathobiology, University of Missouri, Columbia, MO 65211, USA.
Victoria A
VA
Blaho
Matthew W
MW
Buczynski
Edward A
EA
Dennis
Charles R
CR
Brown
D000818:Animals; D000907:Antibodies, Bacterial / Q000096:biosynthesis / Q000145:classification; D016175:B-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology / Q000382:microbiology; D025065:Borrelia burgdorferi / Q000276:immunology; D002478:Cells, Cultured; D051545:Cyclooxygenase 1 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000172:deficiency / Q000378:metabolism; D005260:Female; D018858:Germinal Center / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D017578:Immunoglobulin Class Switching / Q000235:genetics; D007074:Immunoglobulin G / Q000096:biosynthesis; D007075:Immunoglobulin M / Q000096:biosynthesis; D020381:Interleukin-17 / Q000008:administration & dosage / Q000096:biosynthesis / Q000378:metabolism*; D008193:Lyme Disease / Q000201:enzymology / Q000276:immunology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D000907:Antibodies, Bacterial; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D020381:Interleukin-17; D008565:Membrane Proteins; C077623:Ptgs2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496512:Ptgs1 protein, mouse