Interleukin-10 (IL-10) selectively enhances CIS3/SOCS3 mRNA expression in human neutrophils: Evidence for an IL-10-induced pathway that is independent of STAT protein activation

We have recently shown that, in human neutrophils, interleukin-10 (IL-10) f ails to induce specific DNA-binding activities to the gamma-interferon resp onse region (GRR), a regulatory element located in the Fc gamma RI gene pro moter, which is required for transcriptional activation by IL-10 and interf eron gamma (IFN gamma) in monocytic cells. In this study, we report that IL -10 is also unable to induce the binding of STAT1 or STAT3 to the serum-ind ucible element (hSIE/m67), despite the fact that both proteins are expresse d in neutrophils. Whereas IFN gamma and granulocyte colony-stimulating fact or (G-CSF) are efficient inducers of STAT1 and STAT3 tyrosine phosphorylati on in polymorphonuclear neutrophils (PMN), IL-10 fails to trigger STAT1 and STAT3 tyrosine and serine phosphorylation, therefore explaining its inabil ity to induce the Fc gamma RI expression in these cells. By contrast, we de monstrate that IL-10 alone represents an efficient stimulus of CIS3/SOCS3 m RNA expression in neutrophils. CIS3/SOCS3 belongs to the recently cloned cy tokine-inducible SH2-containing protein (CIS) gene family (which also inclu des CIS1, CIS2, CIS4, CIS5, and JAB) that is believed to be, at least in pa rt, under the control of STAT transcription factors and whose products are potential modulators of cytokine signaling. Moreover, IL-10 synergizes with lipopolysaccharide (LPS) in upregulating CIS3/SOCS3 mRNA expression in PMN through a mechanism that involves mRNA stabilization. in contrast to C1S3/ SOCS3, mRNA transcripts encoding other family members are unaffected by IL- 10 in neutrophils. Finally, transfection of CIS3/SOCS3 in murine M1 myeloid cells suppresses LPS-induced growth arrest, macrophage-like differentiatio n, and nitric oxide synthesis, but not IL-6 mRNA expression. Collectively, our data suggest that, in neutrophils, the activation of STAT1 and STAT3 ph osphorylation is neither required for CIS3/SOCS3 induction by IL-10 nor inv olved in the regulatory effects of IL-10 on cytokine production. (C) 1999 b y The American Society of Hematology.