Prostaglandins regulate melanoma-induced cytokine production in macrophages

Tumor-secreted products can affect macrophage cytokine expression and in th at way alter the immune response. Prostaglandins (PGs) are found in the tum or microenvironment and have been associated with local and regional immuno suppression. We investigated whether tumor-secreted factors could induce PG synthesis in macrophages and whether these PGs could alter macrophage prod uction of immunoregulatory cytokines. In both murine and human models, mela noma conditioned medium (MCM) induced macrophage production of PGE(2), IL-6 , and TNF-alpha. PGE(2) production increased over 24 h and was accompanied by an increase in cyclooxygenase-g (COX-2) expression, while COX-1 expressi on remained unchanged. In the presence of 10 muM NS398, a selective COX-2 i nhibitor, MCM-stimulated PGE(2) synthesis was almost completely suppressed, while production of IL-6 and TNF-alpha proteins and mRNA also was partiall y abrogated. In the murine model, 200 muM NS398 resulted in more significan t inhibition of cytokine protein and mRNA production. Although MCM induced NF kappaB and NF-IL-6 activation, neither dose of NS398 altered this effect . We conclude that melanoma-secreted products stimulate COX-2 expression an d PGE(2) synthesis in macrophages and that inhibition of COX-2-derived PG s ynthesis results in partial abrogation of macrophage cytokine production. ( C) 2000 Academic Press.