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Paclitaxel Enhances Macrophage IL-12 Production in Tumor-Bearing Hosts Through Nitric Oxide¹

Department of Biology, Microbiology and Immunology Section, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061

Tumor-induced macrophages (Ms) mediate immunosuppression, in part, through increased production of factors that suppress T cell responsiveness and underproduction of positive regulatory cytokines. Pretreatment of tumor-bearing host (TBH) Ms with the anticancer agent paclitaxel (Taxol) partially reverses tumor-induced M suppressor activity, suggesting that paclitaxel may restore TBH M production of proimmune factors. Because paclitaxel demonstrates LPS-mimetic capabilities and increased production of the LPS-induced immunostimulatory cytokine IL-12 could account for enhanced T cell responsiveness, we investigated whether paclitaxel induces M IL-12 production. Tumor growth significantly down-regulated M IL-12 p70 production through selective dysregulation of IL-12 p40 expression. LPS stimulation failed to overcome tumor-induced dysregulation of p40 expression. In contrast, paclitaxel significantly enhanced both normal host and TBH M IL-12 p70 production in vitro, although TBH M IL-12 production was lower than that of similarly treated normal host Ms. Paclitaxel enhanced p40 expression in a dose-dependent manner. Through reconstituted M IL-12 expression, paclitaxel pretreatment relieved tumor-induced M suppression of T cell alloreactivity. Blocking M NO suppressed paclitaxel’s ability to induce IL-12 production. This suggests that paclitaxel-induced activities may involve a NO-mediated autocrine induction pathway. Collectively, these data demonstrate that paclitaxel restores IL-12 production in the TBH and ascribe a novel immunotherapeutic component to the pleiotropic activities of NO. Through its capacity to induce IL-12 production, paclitaxel may contribute to the correction of tumor-induced immune dysfunction.

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