High affinity receptor for IgG (Fc gamma RI/CD64) gene and STAT protein binding to the IFN-gamma response region (GRR) are regulated differentially in human neutrophils and monocytes by IL-10.
Since IL-10 has been shown to up-regulate the expression of the high affinity receptor for IgG (FcgammaRI/CD64) in human monocytes, we examined whether the cytokine exerts a similar action toward polymorphonuclear neutrophils (PMN). Unexpectedly, we found that in neutrophils, IL-10 failed to induce either the mRNA accumulation or the surface expression of FcgammaRI. Consistent with these findings, stimulation of PMN with IFN-gamma, but not with IL-10, resulted in the induction of specific DNA-binding activities to the IFN-gamma response region (GRR), a regulatory element located in the FcgammaRI gene promoter, required for transcriptional activation. In electrophoretic mobility shift assays (EMSAs), we confirmed that in PBMC, IL-10 induces the binding to the GRR of both STAT1 and STAT3, two members of the STAT family. In neutrophils, however, these activators did not bind to the GRR in response to IL-10, despite the fact that both STAT1 and STAT3 are expressed in these cells. On the other hand, IFN-gamma was an efficient inducer of STAT1 binding to the GRR in both PMN and PBMC. The lack of inducible GRR-binding activity in IL-10-treated PMN could not be ascribed to a lack of IL-10R, and did not appear to reflect an inhibitory effect of the cytokine. Taken together, our data suggest that IL-10 is unable to induce FcgammaRI gene expression in neutrophils because the intracellular signaling pathway triggered by the cytokine is impaired at the level of, or upstream of, STAT1 and/or STAT3 activation.
Bovolenta
C
C
Department of General Pathology, University of Verona, Italy.
Gasperini
S
S
McDonald
P P
PP
Cassatella
M A
MA
D004268:DNA-Binding Proteins / Q000378:metabolism*; D005803:Genes, Immunoglobulin; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics* / Q000494:pharmacology; D016753:Interleukin-10 / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D017452:Receptors, IgG / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D018123:Receptors, Interleukin / Q000096:biosynthesis; D053701:Receptors, Interleukin-10; D012045:Regulatory Sequences, Nucleic Acid / Q000276:immunology*; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000276:immunology; D015534:Trans-Activators / Q000378:metabolism*
D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D017452:Receptors, IgG; D018123:Receptors, Interleukin; D053701:Receptors, Interleukin-10; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D016753:Interleukin-10; D007371:Interferon-gamma