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IL-6 down-modulates the cytokine-enhanced antileishmanial activity in human macrophages
D E Hatzigeorgiou1, S He, J Sobel
1Department of Medicine, Cornell University Medical College, New York, NY 10021.
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.
Insights
Interleukin-6 (IL-6) suppresses the activation of human macrophages (M phi) by pro-inflammatory cytokines like interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). This inhibition affects the M phi
Area of Science:
- Immunology
- Cell Biology
- Parasitology
Background:
- Interleukin-6 (IL-6) is a pleiotropic cytokine with known pro-inflammatory roles.
- Macrophages (M phi) are key immune cells involved in pathogen killing.
- Cytokines like IFN-gamma and TNF-alpha activate M phi for antimicrobial functions.
Purpose of the Study:
- To investigate the in vitro effects of IL-6 on the activation of human M phi by cytokines.
- To determine if IL-6 modulates M phi's capacity to kill Leishmania amazonensis.
- To elucidate the mechanisms by which IL-6 affects M phi activation.
Main Methods:
- Human M phi were pretreated with recombinant human IL-6.
- M phi activation was assessed by their ability to kill L. amazonensis and by measuring oxidative capacity.
- Effects of IL-6 were evaluated in response to IFN-gamma, TNF-alpha, IL-3, GM-CSF, and IL-1 beta.
Main Results:
- IL-6 pretreatment dose- and time-dependently suppressed IFN-gamma and TNF-alpha activation of M phi against L. amazonensis.
- IL-6 inhibited M phi activation by IL-3, GM-CSF, and IL-1 beta, but not IFN-gamma's effect on oxidative capacity.
- IL-6 down-modulated TNF-alpha-induced enhancement of M phi oxidative capacity.
Conclusions:
- IL-6 inhibits cytokine-mediated activation of human M phi for antileishmanial activity.
- This suppression involves both oxygen-dependent and oxygen-independent mechanisms.
- IL-6 plays a regulatory role in M phi's response to inflammatory stimuli.