Differential regulation of IL-1 production in human monocytes by IFN-gamma and IL-4.
We have demonstrated that IL-4 markedly inhibits IL-1 production by highly purified normal human monocytes. When added to monocyte cultures, IL-4 suppressed LPS-induced IL-1 production in a time- and dose-dependent manner. Concentrations of IL-4 as low as 100 pg/ml reduced IL-1 production by approximately 50%, and doses of 1 ng/ml or higher suppressed IL-1 production by more than 90%. Maximal inhibition required that IL-4 be added before or simultaneous with LPS. Northern dot blot analyses revealed that IL-4 not only dramatically reduced the steady-state IL-1 beta mRNA levels in LPS-stimulated monocytes, but also those of TNF-alpha and IL-6. The inhibitory effect was not stimulus-specific because IL-4 suppressed IL-1 production induced by a variety of monocyte activation stimuli, including LPS, PMA, and Staphylococcus aureus Cowan strain. Monocytes expressed a relatively small number of high affinity IL-4R (approximately 150/cell; Ka = 3.15 +/- 1.13 x 10(10) M-1) indicating that relatively few receptors are necessary to generate the inhibitory effect. IL-4 enhanced monocyte MHC class II Ag (HLA-DR) expression in a manner similar to that of IFN-gamma. However, although both IFN-gamma and IL-4 up-regulated HLA-DR expression, they exhibited opposite effects on IL-1 production: IFN-gamma significantly enhanced monocyte IL-1 production induced by submaximal concentrations of LPS; whereas, IL-4 suppressed IL-1 production. Moreover, IL-4 largely neutralized the potentiating effect of IFN-gamma suggesting that IL-4 may be an effective antagonist of certain IFN-gamma-induced effects. Together these findings demonstrate that the relative levels of IFN-gamma and IL-4 may profoundly influence the state of monocyte activation by differentially regulating the expression of IL-1.
Donnelly
R P
RP
Division of Cytokine Biology, Food and Drug Administration, Bethesda, MD 20892.
Fenton
M J
MJ
Finbloom
D S
DS
Gerrard
T L
TL
D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D006681:HLA-D Antigens / Q000276:immunology; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000502:physiology*; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000235:genetics; D015847:Interleukin-4 / Q000494:pharmacology / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D019948:Receptors, Interleukin-4; D011975:Receptors, Mitogen / Q000378:metabolism; D013997:Time Factors
D006681:HLA-D Antigens; D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D019948:Receptors, Interleukin-4; D011975:Receptors, Mitogen; D015847:Interleukin-4; D007371:Interferon-gamma