The cysteine-cysteine family of chemokines RANTES, MIP-1alpha, and MIP-1beta induce trypanocidal activity in human macrophages via nitric oxide.
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.
Villalta
F
F
Department of Microbiology, School of Medicine, Meharry Medical College, Nashville, Tennessee 37208, USA. villal67@ccvax.mmc.edu
Zhang
Y
Y
Bibb
K E
KE
Kappes
J C
JC
Lima
M F
MF
D000818:Animals; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000494:pharmacology*; D019742:Chemokines, CC / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008262:Macrophage Activation; D019402:Macrophage Inflammatory Proteins / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000469:parasitology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010587:Phagocytosis; D014349:Trypanosoma cruzi / Q000276:immunology*; D019323:omega-N-Methylarginine / Q000494:pharmacology
D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D019742:Chemokines, CC; D004791:Enzyme Inhibitors; D019402:Macrophage Inflammatory Proteins; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase