IL-4 up-regulates IL-1 receptor antagonist gene expression and its production in human blood monocytes

IL-4 down-regulates the productions of IL-1 and TNF-alpha in human monocytes. We examined whether the productions of IL-1 and a specific receptor antagonist of IL-1 (IL-1Ra) in human blood monocytes were regulated differently. Highly purified blood monocytes, isolated by centrifugal elutriation from healthy donors, were stimulated with LPS in the presence or absence of IL-4, and their productions of IL-1 and IL-1Ra were measured by Northern blot and immunoblot analyses. IL-1 and IL-1Ra were produced by monocytes stimulated with LPS, but not with IL-4 alone. Marked up-regulation by IL-4 of IL-1Ra production in LPS-stimulated monocytes was observed at both the mRNA and protein levels. Maximal expressions of IL-1 beta and IL-1Ra mRNA in LPS-stimulated monocytes were observed 2 h and 8 h, respectively, after stimulation. The enhancement of IL-1Ra production by IL-4 was concluded to be due to enhanced gene transcription, because there was no difference in the half-lives of IL-1Ra mRNA in monocytes cultured with and without IL-4. Up-regulation of IL-1Ra production by IL-4 was also observed in monocytes stimulated with adherent IgG at both the mRNA and protein levels. This unique property of IL-4 may be important in down-regulation of the IL-1-initiated immune and/or inflammatory response, not only directly through inhibition of IL-1 production, but also indirectly through up-regulation of IL-1Ra production.