Prostaglandins Regulate Melanoma-Induced Cytokine Production in Macrophages

Tumor-secreted products can affect macrophage cytokine expression and in that way alter the immune response. Prostaglandins (PGs) are found in the tumor microenvironment and have been associated with local and regional immunosuppression. We investigated whether tumor-secreted factors could induce PG synthesis in macrophages and whether these PGs could alter macrophage production of immunoregulatory cytokines. In both murine and human models, melanoma conditioned medium (MCM) induced macrophage production of PGE2, IL-6, and TNF-α. PGE2 production increased over 24 h and was accompanied by an increase in cyclooxygenase-2 (COX-2) expression, while COX-1 expression remained unchanged. In the presence of 10 μM NS398, a selective COX-2 inhibitor, MCM-stimulated PGE2 synthesis was almost completely suppressed, while production of IL-6 and TNF-α proteins and mRNA also was partially abrogated. In the murine model, 200 μM NS398 resulted in more significant inhibition of cytokine protein and mRNA production. Although MCM induced NFκB and NF-IL-6 activation, neither dose of NS398 altered this effect. We conclude that melanoma-secreted products stimulate COX-2 expression and PGE2 synthesis in macrophages and that inhibition of COX-2-derived PG synthesis results in partial abrogation of macrophage cytokine production.