Tumor cell-derived TGF-β and IL-10 dysregulate paclitaxel-induced macrophage activation

• Published in: Journal of leukocyte biology Vol. 69; no. 1; pp. 129 - 137
• Main Authors: Mullins, David W., Martins, Ryan S., Burger, Carol J., Elgert, Klaus D.
• Format: Journal Article
• Language: English
• Published: United States Society for Leukocyte Biology 01.01.2001
• Subjects: Animals; Antineoplastic Agents, Phytogenic - immunology; Antineoplastic Agents, Phytogenic - pharmacology; Down-Regulation; Drug Interactions; immunosuppression; Interleukin-10 - immunology; Interleukin-10 - pharmacology; interleukin‐12; Macrophage Activation - drug effects; Macrophage Activation - immunology; Mice; Mice, Inbred BALB C; Neoplasms, Experimental - immunology; Neoplasms, Experimental - metabolism; nitric oxide; paclitaxel; Paclitaxel - immunology; Paclitaxel - pharmacology; prostaglandin E2; Transforming Growth Factor beta - immunology; Transforming Growth Factor beta - pharmacology; transforming growth factor-^b; tumor necrosis factor α
• ISSN: 0741-5400; 1938-3673
• DOI: 10.1189/jlb.69.1.129

Paclitaxel (TAXOL™) activates in vitro macrophage (Mø) expression of proinflammatory and cytotoxic mediators, including IL‐12, tumor necrosis factor α (TNF‐α), and nitric oxide (NO). However, tumors dysregulate Mø through soluble suppressor molecules, and it is possible that tumors evade paclitaxel‐mediated immune effector function through the production of immunomodulatory molecules and inhibition of Mø function in situ. Because Mø activation in the tumor microenvironment is a desirable goal of anti‐tumor immunotherapy, we evaluated whether tumor‐derived immunomodulatory factors dysregulate paclitaxel‐mediated Mø activation. Tumor cell‐derived supernatant suppressed paclitaxel's capacity to induce IL‐12, TNF‐α, and NO production by RAW264.7 Mø. Tumor factors also dysregulated paclitaxel‐induced expression of a HIV‐LTR, promoter‐driven luciferase construct in RAW264.7 Mø, suggesting that tumors may inhibit a broad range of Mø functionality. Depletion studies revealed that IL‐10 and transforming growth factor‐β1 (TGF‐β1), but not prostaglandin E2 (PGE2), impaired paclitaxel‐mediated activation, suggesting that abrogation of these factors in situ might restore paclitaxel's activating capacity and enhance anti‐tumor efficacy.