PubMed · 2237530
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M Freyssenon. [GM-CSF. Cellular growth factor].. https://pubmed.ncbi.nlm.nih.gov/2237530/
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Interleukin-10 (IL-10) exerts its anti-inflammatory properties by down-regulating polymorphonuclear neutrophil (PMN) functions such as reactive oxygen species (ROS) production via NADPH oxidase. The molecular mechanisms underlying this process are unclear. Partial phosphorylation of the NADPH oxidase cytosolic component p47(PHOX) induced by proinflammatory cytokines, such as granulocyte-macrophage colony stimulating factor (GM-CSF) and tumor necrosis factor (TNF)-alpha, is essential for priming ROS production by PMN. The aim of this study was to determine whether IL-10 inhibits GM-CSF- and TNFalpha-induced p47(PHOX) phosphorylation and to investigate the molecular mechanisms involved in this effect. We found that IL-10 selectively inhibited GM-CSF- but not TNFalpha-induced p47PHOX phosphorylation in a concentration-dependent manner. As GM-CSF-induced p47PHOX phosphorylation is mediated by extracellular signal-regulated kinase 1/2 (ERK1/2), we tested the effect of IL-10 on this pathway. We found that IL-10 inhibited GM-CSF-induced ERK1/2 activity in an immunocomplex kinase assay. This inhibitory effect was confirmed by analyzing the phosphorylation status of the endogenous substrate of ERK1/2, p90RSK, in intact PMN. Furthermore, IL-10 decreased ROS production by adherent GM-CSF-treated PMN in keeping with the higher ROS production observed in whole blood from IL-10 knockout mice compared to their wild-type counterparts. Together, these results suggest that IL-10 inhibits GM-CSF-induced priming of ROS production by inhibiting p47PHOX phosphorylation through a decrease in ERK1/2 activity. This IL-10 effect could contribute to the tight regulation of NADPH oxidase activity at the inflammatory site.
Csk homologous kinase (Chk) is a tyrosine kinase that shares homology with Csk and, like Csk, has the potential to inhibit src-family kinase function through phosphorylation. In myeloid lineage cells, Chk expression is dependent on monocytic differentiation. IL-4 and IL-13 are cytokines involved in monocytic differentiation that have recently been shown to induce Chk expression in peripheral blood monocytes (PBMs). In this study, we show that two other members of the IL-4 family, IL-3 and GM-CSF, can also induce Chk expression at RNA and protein levels. Interestingly, Chk induction is both blocked and reversed by IFN-gamma treatment. Additionally, a short pretreatment with IFN-gamma is sufficient to prevent Chk induction, and the effects of IFN-gamma are dependent on protein synthesis. Collectively, these results suggest that activation of Chk expression and signaling may have a role in the IL-4 family-mediated differentiation of myeloid cells, and inhibition of Chk activation may be one mechanism by which IFN-gamma alters IL-4-mediated affects.
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