Prostaglandin E2 Induction Suppresses the Th1 Immune Responses in Cattle with Johne's Disease

Johne's disease, caused by Mycobacterium avium subsp. paratuberculosis, is a bovine chronic infection that is endemic in Japan and many other countries. The expression of immunoinhibitory molecules is upregulated in cattle with Johne's disease, but the mechanism of immunosuppression is poorly understood. Prostaglandin E-2 (PGE(2)) is immunosuppressive in humans, but few veterinary data are available. In this study, functional and kinetic analyses of PGE(2) were performed to investigate the immunosuppressive effect of PGE(2) during Johne's disease. In vitro PGE(2) treatment decreased T-cell proliferation and Th1 cytokine production and upregulated the expression of immunoinhibitory molecules such as interleukin-10 and programmed death ligand 1 (PD-L1) in peripheral blood mononuclear cells (PBMCs) from healthy cattle. PGE(2) was upregulated in sera and intestinal lesions of cattle with Johne's disease. In vitro stimulation with Johnin purified protein derivative (JPPD) induced cyclooxygenase-2 (COX-2) transcription, PGE(2) production, and upregulation of PD-L1 and immunoinhibitory receptors in PBMCs from cattle infected with M. avium subsp. paratuberculosis. Therefore, Johnin-specific Th1 responses could be limited by the PGE(2) pathway in cattle. In contrast, downregulation of PGE(2) with a COX-2 inhibitor promoted J-PPD-stimulated CD8(+) T-cell proliferation and Th1 cytokine production in PBMCs from the experimentally infected cattle. PD-L1 blockade induced J-PPD-stimulated CD8(+) T-cell proliferation and interferon gamma production in vitro. Combined treatment with a COX-2 inhibitor and anti-PD-L1 antibodies enhanced J-PPD-stimulated CD8(+) T-cell proliferation in vitro, suggesting that the blockade of both pathways is a potential therapeutic strategy to control Johne's disease. The effects of COX-2 inhibition warrant further study as a novel treatment of Johne's disease.