IL-6 down-modulates the cytokine-enhanced antileishmanial activity in human macrophages.
IL-6 is a cytokine synthesized by T cells and macrophages (M phi). It has 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 M phi, experiments were carried out to investigate the in vitro effects of recombinant human IL-6 on cytokine activation of human M phi. Pretreatment with IL-6 induced a dose- and time-dependent suppression of IFN-gamma (1000 U/mL) and TNF-alpha (25 ng/mL) activation of M phi for the killing of L. amazonensis. At doses greater than 0.1 to 100 ng/mL, IL-6 inhibited IFN-gamma and TNF-alpha activation by 21 to 93% and 36 to 82%, respectively. IL-6 alone had no effect on M phi viability and intracellular L. amazonensis growth. Blockade of M phi 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 M phi activation for antileishmanial capacity by IL-3, granulocyte-monocyte-CSF (GM-CSF) and IL-1 beta. Because cytokine induction of antileishmanial activity is associated with enhancement of oxidative capacity, the effect of IL-6 on this mechanism was evaluated. Pretreatment with IL-6 down-modulated TNF-alpha (25 ng/mL) enhancement of M phi oxidative capacity in a dose- and time-dependent manner. A similar depression of oxidative capacity was observed for GM-CSF and IL-3 but not for IFN-gamma. Furthermore, NG-monomethyl-L-arginine (a nitric oxide synthase inhibitor) had no effect on IFN-gamma and TNF-alpha activation of antileishmanial activity and nitrites/nitrates were not reliably assayed from M phi culture supernatants. These findings suggest that IL-6 down-modulates cytokine activation of M phi antileishmanial capacity by inhibiting oxygen-dependent and undefined oxygen-independent mechanisms.
Department of Medicine, Cornell University Medical College, New York, NY 10021.
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Hatzigeorgiou
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He
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Sobel
K H
KH
Grabstein
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Hafner
J L
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Ho
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D015536:Down-Regulation; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007377:Interleukin-3 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology*; D007891:Leishmania / Q000187:drug effects / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D009569:Nitric Oxide / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019323:omega-N-Methylarginine
D016207:Cytokines; D007377:Interleukin-3; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D007371:Interferon-gamma; D001120:Arginine