IL-6 down-modulates the cytokine-enhanced antileishmanial activity in human macrophages

J Immunol. 1993 Oct 1;151(7):3682-92.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Arginine / analogs & derivatives
  • Arginine / pharmacology
  • Cells, Cultured
  • Cytokines / pharmacology*
  • Down-Regulation
  • Humans
  • Interferon-gamma / pharmacology
  • Interleukin-3 / pharmacology
  • Interleukin-6 / pharmacology*
  • Leishmania / drug effects
  • Leishmania / immunology*
  • Macrophages / drug effects
  • Macrophages / immunology*
  • Nitric Oxide / metabolism
  • Superoxides / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology
  • omega-N-Methylarginine

Substances

  • Cytokines
  • Interleukin-3
  • Interleukin-6
  • Tumor Necrosis Factor-alpha
  • Superoxides
  • omega-N-Methylarginine
  • Nitric Oxide
  • Interferon-gamma
  • Arginine