Interleukin (IL) 4 differentially regulates monocyte IL-1 family gene expression and synthesis in vitro and in vivo.
Interleukin (IL) 4 is a multifunctional T cell-derived cytokine that inhibits cytokine production and certain effector functions in human monocytes, while enhancing others. We show that IL-4 may contribute to the downregulation and resolution of an inflammatory response by selectively promoting expression of the IL-1 receptor antagonist (IL-1ra) that blocks the action of IL-1. IL-1ra specifically binds to the IL-1 receptor without initiating signal transduction. Peripheral blood monocytes obtained from cancer patients, before and immediately after a regimen of IL-4 immunotherapy, were examined for IL-1ra gene expression. After IL-4 therapy, monocytes from the patients showed a marked increase in IL-1ra mRNA. This selective induction of IL-1ra mRNA in circulating monocytes was reflected by significantly enhanced serum levels of IL-1ra (p < 0.01) during IL-4 therapy, which declined after IL-4 treatment. In vitro analysis of IL-4 regulation of monocytes from normal individuals revealed a dose-dependent induction of IL-1ra mRNA within 2-4 h after stimulation without a concomitant effect on the expression of IL-1 mRNA. Increased IL-1ra mRNA was not due to RNA stabilization, but occurred at the level of transcription. In the presence of LPS, IL-4 not only augmented IL-1ra levels, but markedly inhibited LPS-induced IL-1 mRNA expression. The selective upregulation of IL-1ra by resting or activated monocytes, coupled with inhibition of IL-1 production by activated monocytes, as we demonstrate both in vitro and in vivo, suggests that IL-4 may prove clinically useful as a systemic antiinflammatory agent.
Wong
H L
HL
Laboratory of Immunology, National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland 20892.
Costa
G L
GL
Lotze
M T
MT
Wahl
S M
SM
D015152:Blotting, Northern; D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000502:physiology; D015870:Gene Expression / Q000235:genetics*; D006801:Humans; D007167:Immunotherapy; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics*; D015847:Interleukin-4 / Q000494:pharmacology*; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D009000:Monocytes / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors; D012795:Sialoglycoproteins / Q000032:analysis / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D014407:Tumor Cells, Cultured
C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D012795:Sialoglycoproteins; D015847:Interleukin-4