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(Journal of Leukocyte Biology. 2001;69:129-137.)
© 2001 by Society for Leukocyte Biology

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

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

Correspondence: Dr. Klaus D. Elgert, Department of Biology, Microbiology and Immunology Section, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061-0406. E-mail: kdelgert{at}vt.edu

Paclitaxel (TAXOL^TM) activates in vitro macrophage (Mø) expression of proinflammatory and cytotoxic mediators, including IL-12, tumor necrosis factor (TNF-), 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-, 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-ß₁ (TGF-ß₁), 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.

Key Words: immunosuppression • tumor necrosis factor • interleukin-12 • prostaglandin E₂ • nitric oxide

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