Immunomodulatory effect of nonsteroidal anti-inflammatory drugs (NSAIDs) at the clinically available doses.
Non-steroidal anti-inflammatory drugs (NSAIDs) with cyclooxygenase (COX) inhibitory activity are commonly used in various inflammatory diseases. In this study, to examine the immunomodulatory effects of well known NSAIDs at clinically available doses, macrophage- and T cell-mediated immune responses such as tumor necrosis factor (TNF)-alpha release and nitric oxide (NO) production, cell-cell adhesion, phagocytic uptake and lymphocyte proliferation were investigated. NSAIDs tested significantly enhanced TNF-alpha release from lipopolysaccharide (LPS)-activated RAW264.7 cells at certain concentrations (fenoprofen, indomethacin, piroxicam, aceclofenac, diclofenac and sulindac) or in a dose-dependent manner (aspirin and phenylbutazone). Of NSAIDs, phenylbutazone and aspirin most potently attenuated NO production, although sulindac was the only compound with cytoprotective activity against LPS-induced cytotoxicity. Most NSAIDs used displayed weak or no modulatory effects on phagocytic uptake and CD29- or CD43-mediated cell-cell adhesion. Interestingly, however, phenylbutazone itself triggered cell-cell clustering under normal culture conditions and enhanced the phagocytic activity. Aspirin and phenylbutazone also dose-dependently attenuated CD4+ T cell proliferation stimulated by concanavalin A (Con A) and CD8+ CTLL-2 cell proliferation induced by interleukin (IL)-2. Sulindac only blocked CTLL-2 cell proliferation. These results suggest that NSAIDs may differentially exert immunomodulatory effects on activated macrophages and lymphocytes, and some of the effects may enforce NSAID's therapeutic effect against inflammatory symptoms.
Cho
Jae Youl
JY
School of Bioscience and Biotechnology and Korean Nutritional Science Institute, Kangwon National University, Chuncheon 200-701, Korea. jaecho@kangwon.ac.kr
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D002449:Cell Aggregation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology* / Q000627:therapeutic use; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020298:U937 Cells
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D007155:Immunologic Factors; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D051546:Cyclooxygenase 2