IFN-alpha and IL-18 exert opposite regulatory effects on the IL-12 receptor expression and IL-12-induced IFN-gamma production in mouse macrophages: novel pathways in the regulation of the inflammatory response of macrophages.
We characterized the IL-12 response of mouse macrophages in terms of modulation of IFN-gamma production by cytokines (IFN-alpha and IL-18) and regulation of IL-12 receptor expression. Beta1 and beta2 IL-12R chain mRNA expression increased with time in culture in the absence of exogenous stimulation, with concomitant acquisition of responsiveness to IL-12 for IFN-gamma production. Expression of the IL-12R beta1 chain mRNA was increased further following IL-12 treatment as a consequence of IFN-gamma expression. IL-12 response was regulated differentially by IFN-alpha and IL-18. Neutralization of endogenous type I IFN increased IFN-gamma secretion, whereas exogenous IFN-alpha reduced it. In contrast, IL-18 enhanced IFN-gamma mRNA accumulation and IFN-gamma secretion in IL-12-stimulated, but not -untreated, cultures. The opposite effects exerted by IFN-alpha and IL-18 mirror their mutual capacity of regulating-in a negative or positive manner, respectively-the expression of the IL-12R beta1 chain. We suggest that differential regulation of IL-12 response by IFN-alpha and IL-18 can represent previously unrecognized regulatory mechanisms for maintaining suitable levels of differentiation/activation in macrophages.
Fantuzzi
L
L
Laboratory of Virology, Istituto Superiore di Sanità, Rome, Italy.
Puddu
P
P
Varano
B
B
Del Cornò
M
M
Belardelli
F
F
Gessani
S
S
D000818:Animals; D002478:Cells, Cultured; D004357:Drug Synergism; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D007370:Interferon Type I / Q000096:biosynthesis / Q000494:pharmacology* / Q000502:physiology; D007371:Interferon-gamma / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D020382:Interleukin-18 / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D018123:Receptors, Interleukin / Q000096:biosynthesis*; D053707:Receptors, Interleukin-12; D011994:Recombinant Proteins / Q000494:pharmacology
C508440:Il12rb1 protein, mouse; C508443:Il12rb2 protein, mouse; D007370:Interferon Type I; D020382:Interleukin-18; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D011994:Recombinant Proteins; D018664:Interleukin-12; D007371:Interferon-gamma