International Immunology, Vol. 14, No. 10, pp. 1145-1153,
October 2002
© 2002 Japanese Society for Immunology
Molecular basis of the synergistic production of IL-1 receptor antagonist by human neutrophils stimulated with IL-4 and IL-10
1 Department of Pathology, General Pathology Unit, University of Verona, Strada Le Grazie 4, 37134 Verona, Italy
Correspondence to: M. A. Cassatella; E-mail: marco.cassatella{at}univr.it
Transmitting editor: G. Trinchieri
In this study, we report that the release of IL-1 receptor antagonist (IL-1ra) from IL-4-stimulated neutrophils is markedly enhanced in the presence of IL-10. We also show that up-regulation of IL-1ra release by IL-10 in IL-4-stimulated neutrophils takes place through IL-1ra mRNA stabilization and enhancement of IL-1ra de novo synthesis. Furthermore, we report that the ability of IL-10 to up-regulate IL-1ra mRNA expression in IL-4-treated neutrophils requires 56 h and it is preceded by the acquisition of the capacity to activate Stat3 tyrosine phosphorylation. This latter response to IL-10 was strictly dependent on the levels of expression of IL-10R1, which were in fact significantly increased by IL-4 in cultured neutrophils via a signaling pathway sensitive to the serine/threonine kinase inhibitor H-7. Collectively, our data emphasize the central role of IL-10R1 expression in regulating cell responsiveness to IL-10. In addition, the fact that IL-10 strongly up-regulates IL-1ra production in IL-4-activated neutrophils uncovers a novel mechanism whereby IL-10 and IL-4 cooperate to negatively modulate the inflammatory responses.
Keywords: IL-10R1, lipopolysaccharide, STAT3
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