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IL-15 functions as a potent autocrine regulator of macrophage proinflammatory cytokine production: evidence for differential receptor subunit utilization associated with stimulation or inhibition.

D G Alleva, S B Kaser, M A Monroy, M J Fenton and D I Beller
J Immunol September 15, 1997, 159 (6) 2941-2951;
D G Alleva
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S B Kaser
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M A Monroy
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M J Fenton
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D I Beller
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Abstract

The cytokine IL-15 appears to mimic the stimulatory activity of IL-2 on lymphocytes by utilizing part of the IL-2R complex. Although effects of IL-15 on Mphi activities have not previously been reported, its derivation from activated Mphi suggested a possible autocrine role in regulating Mphi functions and prompted us to determine whether IL-15 modulated LPS-activated Mphi cytokine production. Whereas high IL-15 concentrations enhanced proinflammatory (i.e., TNF-alpha, IL-1, and IL-6) and anti-inflammatory (i.e., IL-10) cytokine production by two- to sixfold, extremely low IL-15 concentrations (picomolar to attomolar range) markedly and selectively suppressed Mphi proinflammatory, but not anti-inflammatory, cytokine production by two- to fourfold. The stimulation (but not the suppression) of TNF-alpha production by IL-15 required the (IL-2/IL-15) receptor beta chain, as demonstrated by receptor subunit-blocking studies and lack of stimulation of Mphi from IL-2Rbeta-deficient mice. Conversely, suppression most likely involved the alpha receptor (IL-15R alpha) because this high affinity receptor would be engaged by low concentrations of IL-15, and its inducible expression correlated with the degree of suppression in both a time- and LPS dose-dependent fashion. Moreover, Ab-mediated neutralization studies revealed that endogenous IL-15 activity regulated Mphi activation with kinetics similar to that seen in response to exogenously added IL-15: suppressor activity increased over time in correlation with IL-15R alpha gene expression. This study demonstrates a novel dose-dependent and autocrine activity of IL-15 in Mphi regulation.

  • Copyright © 1997 by American Association of Immunologists

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The Journal of Immunology
Vol. 159, Issue 6
15 Sep 1997
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IL-15 functions as a potent autocrine regulator of macrophage proinflammatory cytokine production: evidence for differential receptor subunit utilization associated with stimulation or inhibition.
D G Alleva, S B Kaser, M A Monroy, M J Fenton, D I Beller
The Journal of Immunology September 15, 1997, 159 (6) 2941-2951;

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IL-15 functions as a potent autocrine regulator of macrophage proinflammatory cytokine production: evidence for differential receptor subunit utilization associated with stimulation or inhibition.
D G Alleva, S B Kaser, M A Monroy, M J Fenton, D I Beller
The Journal of Immunology September 15, 1997, 159 (6) 2941-2951;
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Print ISSN 0022-1767        Online ISSN 1550-6606