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The expression of immunoinhibitory molecules is upregulated in cattle with Johne's disease, but the mechanism of immunosuppression is poorly understood. Prostaglandin E<jats:sub>2<\/jats:sub>(PGE<jats:sub>2<\/jats:sub>) is immunosuppressive in humans, but few veterinary data are available. In this study, functional and kinetic analyses of PGE<jats:sub>2<\/jats:sub>were performed to investigate the immunosuppressive effect of PGE<jats:sub>2<\/jats:sub>during Johne's disease.<jats:italic>In vitro<\/jats:italic>PGE<jats:sub>2<\/jats:sub>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<jats:sub>2<\/jats:sub>was upregulated in sera and intestinal lesions of cattle with Johne's disease.<jats:italic>In vitro<\/jats:italic>stimulation with Johnin purified protein derivative (J-PPD) induced cyclooxygenase-2 (COX-2) transcription, PGE<jats:sub>2<\/jats:sub>production, and upregulation of PD-L1 and immunoinhibitory receptors in PBMCs from cattle infected with<jats:named-content content-type=\"genus-species\">M. avium<\/jats:named-content>subsp.<jats:named-content content-type=\"genus-species\">paratuberculosis<\/jats:named-content>. Therefore, Johnin-specific Th1 responses could be limited by the PGE<jats:sub>2<\/jats:sub>pathway in cattle. In contrast, downregulation of PGE<jats:sub>2<\/jats:sub>with a COX-2 inhibitor promoted J-PPD-stimulated CD8<jats:sup>+<\/jats:sup>T-cell proliferation and Th1 cytokine production in PBMCs from the experimentally infected cattle. PD-L1 blockade induced J-PPD-stimulated CD8<jats:sup>+<\/jats:sup>T-cell proliferation and interferon gamma production<jats:italic>in vitro<\/jats:italic>. Combined treatment with a COX-2 inhibitor and anti-PD-L1 antibodies enhanced J-PPD-stimulated CD8<jats:sup>+<\/jats:sup>T-cell proliferation<jats:italic>in vitro<\/jats:italic>, 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.<\/jats:p>","DOI":"10.1128\/iai.00910-17","type":"journal-article","created":{"date-parts":[[2018,2,23]],"date-time":"2018-02-23T10:07:45Z","timestamp":1519380465000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":28,"title":["Prostaglandin E<sub>2<\/sub>Induction Suppresses the Th1 Immune Responses in Cattle with Johne's Disease"],"prefix":"10.1128","volume":"86","author":[{"given":"Yamato","family":"Sajiki","sequence":"first","affiliation":[{"name":"Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoru","family":"Konnai","sequence":"additional","affiliation":[{"name":"Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, 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