IL-6 DOWN-MODULATES THE CYTOKINE-ENHANCED ANTILEISHMANIAL ACTIVITY INHUMAN MACROPHAGES

IL-6 is a cytokine synthesized by T cells and macrophages (Mphi). It h as pleiotropic effects on diverse cell types and is recognized for its ''pro-inflammatory'' properties. In mice, IL-4, IL-5, IL-6, and IL-10 are produced by Th-2 cells. Because IL-10 suppresses Th-1 clones, and IL-4 broadly deactivates Mphi, experiments were carried out to invest igate the in vitro effects of recombinant human IL-6 on cytokine activ ation of human Mphi. Pretreatment with IL-6 induced a dose- and time-d ependent suppression of IFN-gamma (1000 U/mL) and TNF-alpha (25 ng/mL) activation of Mphi for the killing of L. amazonensis. At doses greate r than 0.1 to 100 ng/mL, IL-6 inhibited IFN-gamma and TNF-alpha activa tion by 21 to 93% and 36 to 82%, respectively. IL-6 alone had no effec t on Mphi viability and intracellular L. amazonensis growth. Blockade of Mphi activation was greatest when IL-6 was added 24 or 48 h before infection and treatment with IFN-gamma or TNF-alpha. Furthermore, mAb against IL-6 abrogated the inhibitory activity of IL-6. Similarly IL-6 pretreatment suppressed Mphi activation for antileishmanial capacity by IL-3, granulocyte-monocyte-CSF (GM-CSF) and IL-1 beta. Because cyto kine induction of antileishmanial activity is associated with enhancem ent of oxidative capacity, the effect of IL-6 on this mechanism was ev aluated. Pretreatment with IL-6 down-modulated TNF-alpha (25 ng/mL) en hancement of Mphi oxidative capacity in a dose- and time-dependent man ner. A similar depression of oxidative capacity was observed for GM-CS F and IL-3 but not for IFN-gamma. Furthermore, N(G)-monomethyl-L-argin ine (a nitric oxide synthase inhibitor) had no effect on IFN-gamma and TNF-alpha activation of antileishmanial activity and nitrites/nitrate s were not reliably assayed from Mphi culture supernatants. These find ings suggest that IL-6 down-modulates cytokine activation of Mphi anti leishmanial capacity by inhibiting oxygen-dependent and undefined oxyg en-independent mechanisms.