Cyclooxygenase-1 and -2 Play Contrasting Roles in Listeria-Stimulated Immunity.

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) activity and are commonly used for pain relief and fever reduction. NSAIDs are used following childhood vaccinations and cancer immunotherapies; however, how NSAIDs influence the development of immunity following these therapies is unknown. We hypothesized that NSAIDs would modulate the development of an immune response to Listeria monocytogenes-based immunotherapy. Treatment of mice with the nonspecific COX inhibitor indomethacin impaired the generation of cell-mediated immunity. This phenotype was due to inhibition of the inducible COX-2 enzyme, as treatment with the COX-2-selective inhibitor celecoxib similarly inhibited the development of immunity. In contrast, loss of COX-1 activity improved immunity to L. monocytogenes Impairments in immunity were independent of bacterial burden, dendritic cell costimulation, or innate immune cell infiltrate. Instead, we observed that PGE2 production following L. monocytogenes is critical for the formation of an Ag-specific CD8+ T cell response. Use of the alternative analgesic acetaminophen did not impair immunity. Taken together, our results suggest that COX-2 is necessary for optimal CD8+ T cell responses to L. monocytogenes, whereas COX-1 is detrimental. Use of pharmacotherapies that spare COX-2 activity and the production of PGE2 like acetaminophen will be critical for the generation of optimal antitumor responses using L. monocytogenes.

• Authors: Erin Theisen, Courtney E McDougal, Masako Nakanishi, David M Stevenson, Daniel Amador-Noguez, Daniel W Rosenberg, Laura J Knoll, John-Demian Sauer
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 200 Issue 11 Pg. 3729-3738 (06 01 2018) ISSN: 1550-6606 [Electronic] United States
• PMID: 29678951 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2018 by The American Association of Immunologists, Inc.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Cyclooxygenase 2 Inhibitors
• Membrane Proteins
• Acetaminophen
• Cyclooxygenase 1
• Cyclooxygenase 2
• Ptgs1 protein, mouse
• Dinoprostone

Topics

• Acetaminophen (pharmacology)
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (immunology, pharmacology)
• CD8-Positive T-Lymphocytes (drug effects, immunology)
• Cyclooxygenase 1 (immunology)
• Cyclooxygenase 2 (immunology)
• Cyclooxygenase 2 Inhibitors (pharmacology)
• Dinoprostone (immunology)
• Female
• Immunity (immunology)
• Immunity, Innate (drug effects, immunology)
• Listeria monocytogenes (immunology)
• Listeriosis (immunology)
• Male
• Membrane Proteins (immunology)
• Mice
• Mice, Inbred C57BL