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Infection and Immunity, October 1998, p. 4690-4695, Vol. 66, No. 10
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

The Cysteine-Cysteine Family of Chemokines RANTES, MIP-1alpha , and MIP-1beta Induce Trypanocidal Activity in Human Macrophages via Nitric Oxide

Fernando Villalta,1,* Yuan Zhang,1 Kartz E. Bibb,1 John C. Kappes,2 and Maria F. Lima1

Department of Microbiology, School of Medicine, Meharry Medical College, Nashville, Tennessee 37208,1 and Department of Medicine and Microbiology, University of Alabama at Birmingham, Birmingham, Alabama 352942

Received 23 March 1998/Returned for modification 19 May 1998/Accepted 23 July 1998

This paper describes a new role for the cysteine-cysteine (CC) chemokines RANTES, MIP-1alpha , and MIP-1beta on human macrophage function, which is the induction of nitric oxide (NO)-mediated trypanocidal activity. In a previous report, we showed that RANTES, MIP-1alpha and MIP-1beta enhance Trypanosoma cruzi uptake and promote parasite killing by human macrophages (M. F. Lima, Y. Zhang, and F. Villalta, Cell. Mol. Biol. 43:1067-1076, 1997). Here we study the mechanism by which RANTES, MIP-1alpha , and MIP-1beta activate human macrophages obtained from healthy individuals to kill T. cruzi. Treatment of human macrophages with different concentrations of RANTES, MIP-1alpha , and MIP-1beta enhances T. cruzi trypomastigote phagocytosis in a dose peak response. The optimal response induced by the three CC chemokines is attained at 500 ng/ml. The macrophage trypanocidal activity induced by CC chemokines can be completely inhibited by L-N-monomethyl arginine (L-NMMA), a specific inhibitor of the L-arginine:NO pathway, but not by its D-enantiomer. Culture supernatants of chemokine-treated human macrophages contain increased NO2- levels, and NO2- production is also specifically inhibited by L-NMMA. The amount of NO2- induced by these chemokines in human macrophages is comparable to the amount of NO2- induced by gamma interferon. The killing of trypomastigotes by NO in cell-free medium is blocked by an NO antagonist or a NO scavenger. This data supports the hypothesis that the CC chemokines RANTES, MIP-1alpha , and MIP-1beta activate human macrophages to kill T. cruzi via NO, which is an effective trypanocidal mechanism.

* Corresponding author. Mailing address: Department of Microbiology, Meharry Medical College, 1005 D. B. Todd, Jr. Blvd., Nashville, TN 37208. Phone: (615) 327-6173. Fax: (615) 321-2999. E-mail: villal67{at}ccvax.mmc.edu.

Infection and Immunity, October 1998, p. 4690-4695, Vol. 66, No. 10
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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