IL-15 functions as a potent autocrine regulator of macrophage proinflammatory cytokine production: evidence for differential receptor subunit utilization associated with stimulation or inhibition.
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.
Alleva
D G
DG
Evans Memorial Department of Clinical Research, Boston University Medical Center, MA 02118, USA. dgalleva@bu.edu
Kaser
S B
SB
Monroy
M A
MA
Fenton
M J
MJ
Beller
D I
DI
D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D019409:Interleukin-15 / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2 / Q000378:metabolism*; D015398:Signal Transduction
D016207:Cytokines; C508025:Il15ra protein, mouse; D019409:Interleukin-15; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2