Immune modulatory effects of indomethacin in melanoma patients are not related to prostaglandin E2-mediated suppression.
Indomethacin significantly enhances the depressed levels of lymphocyte proliferation to the mitogens phytohemagglutinin and concanavalin A in melanoma patients. We postulated that these results were related to an abnormality in prostaglandin E2 (PGE2)-mediated suppression, since this mechanism has previously has previously been demonstrated in patients with Hodgkin's lymphoma and with head and neck carcinoma. However, the results of three experimental approaches did not support this hypothesis. First, in vitro PGE2 production by cultured blood mononuclear cells was the same in 16 melanoma patients as in 45 normal controls (4.9 versus 4.7 ng/ml). Second, lymphocyte sensitivity to PGE2 for melanoma patients was essentially the same as that for normal controls, since exogenous doses of PGE2 inhibited the mitogen responses to the same degree. Third, another prostaglandin synthetase inhibitor (RO-205720), which is structurally unrelated to indomethacin, did not augment the mitogen response in these patients. Thus PGE2 cannot be implicated as a mediator of immunosuppression in melanoma patients. To further examine the immunomodulatory mechanism of indomethacin, we preincubated the drug with purified populations of either lymphocytes or monocytes, which were then recombined and tested for mitogen response. The results suggested that indomethacin had a direct effect on the responding T lymphocytes rather than an indirect effect on monocytes. These are the first studies demonstrating that indomethacin can act directly as a modulator of cellular immune function, independent of PGE2-mediated suppression.
D000328:Adult; D000368:Aged; D002227:Carbazoles / Q000276:immunology / Q000494:pharmacology; D003208:Concanavalin A / Q000276:immunology; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D007109:Immunity / Q000187:drug effects*; D007165:Immunosuppression Therapy; D007213:Indomethacin / Q000494:pharmacology*; D008214:Lymphocytes / Q000187:drug effects; D008545:Melanoma / Q000276:immunology*; D008875:Middle Aged; D010835:Phytohemagglutinins / Q000276:immunology; D011458:Prostaglandins E / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology
D002227:Carbazoles; D010835:Phytohemagglutinins; D011458:Prostaglandins E; D003208:Concanavalin A; D000242:Cyclic AMP; C007005:carprofen; D007213:Indomethacin