Paclitaxel (Taxol)-induced killing of Leishmania major in murine macrophages

Abstract

The antitumor drug paclitaxel (Taxol) has been demonstrated to be a lipopolysaccharide mimetic in murine macrophages. In this study, the capacity of paclitaxel to activate macrophages to become microbicidal for Leishmania major was examined. Paclitaxel and gamma interferon synergized to kill intracellular L. major in Lpsn, but not Lpsd, macrophages by a nitric oxide (NO.)-dependent mechanism.

FIG. 1

Induction of NO· release and L. major killing in C3H/OuJ and C3H/HeJ macrophages by paclitaxel (Tx) or LPS and IFN-γ. Macrophages were treated with combinations of paclitaxel (1 or 10 μM) and/or 5 U of IFN-γ per ml (A and C) or with LPS (protein free) (10 ng/ml) or LPS-But (protein rich) (10 μg/ml) and IFN-γ (B and D) and then infected with L. major. NO· was measured from the supernatants (A and B), and the number of L. major parasites was quantified from macrophage lysates (C and D). Results are derived from a single experiment representative of six separate experiments.

FIG. 2

Time course for induction of NO· release and parasite killing in C3H/OuJ and C3H/HeJ macrophages treated with paclitaxel (10 μM) plus IFN-γ (5 U/ml). Results are derived from a single experiment representative of six separate experiments.

FIG. 3

Effects of L-NMMA on NO· release and killing of L. major in paclitaxel (10 μM)- and IFN-γ (5 U/ml)-treated C3H/OuJ and C3H/HeJ macrophages. Results are derived from a single experiment representative of two separate experiments.

FIG. 4

Induction of NO· release, TNF-α production, and killing of L. major by LPS (10 ng/ml) or paclitaxel (10 μM) and IFN-γ (5 U/ml) in (C57BL/6 × 129)F₁ (+/+) and iNOS KO (−/−) macrophages. Macrophages were treated as described in the legend to Fig. 1.