PubMed · 9109799
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M A Birchall. 1997. Fluticasone.. https://doi.org/10.1001/archotol.1997.01900040101017
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Human neutrophils (PMNs) express two receptors for the Fc domain of IgG: the transmembrane FcgammaRIIA, whose cytosolic sequence contains an immunoreceptor tyrosine-based activation motif, and the GPI-anchored FcgammaRIIIB. Cross-linking of FcgammaRIIIB induces cell activation, but the mechanism is still uncertain. We have used mAbs to cross-link selectively each of the two receptors and to assess their signaling phenotypes and functional relation. Cross-linking of FcgammaRIIIB induces intracellular Ca2+ release and receptor capping. The Ca2+ response is blocked by wortmannin and by N,N-dimethylsphingosine, inhibitors of phosphatidylinositol 3-kinase and sphingosine kinase, respectively. Identical dose-response curves are obtained for the Ca2+ release stimulated by cross-linking FcgammaRIIA, implicating these two enzymes in a common signaling pathway. Wortmannin also inhibits capping of both receptors, but not receptor endocytosis. Fluorescence microscopy in double-labeled PMNs demonstrates that FcgammaRIIA colocalizes with cross-linked FcgammaRIIIB. The signaling phenotypes of the two receptors diverge only under frustrated phagocytosis conditions, where FcgammaRIIIB bound to substrate-immobilized Ab does not elicit cell spreading. We propose that FcgammaRIIIB signaling is conducted by molecules of FcgammaRIIA that are recruited to protein/lipid domains induced by clustered FcgammaRIIIB and, thus, are brought into juxtaposition for immunoreceptor tyrosine-based activation motif phosphorylation and activation of PMNs.
BACKGROUND: A number of recent studies have identified interleukin (IL)-6 as an important regulator of prostate cancer growth. Here, we investigate the potential interaction of IL-6 with phosphatidylinositol (PI)-3 kinase, a key growth regulatory enzyme, in prostate cancer cell lines. METHODS: Tyrosine phosphorylation of p85, the regulatory subunit of PI-3 kinase, in the human prostate cancer cell lines LNCaP and PC-3 was assessed by sequential immunoprecipitation with anti-p85 antibody and immunoblotting with anti-phosphotyrosine. The effects of wortmannin, an inhibitor of PI-3 kinase, and/or IL-6 on cell growth were assessed by MTT assays. DNA laddering experiments were performed to assay for programmed cell death. RESULTS: Tyrosine phosphorylation of p85 is upregulated by IL-6 in both LNCaP and PC-3. IL-6 promotes coprecipitation of p85 with gp130, the signal-transducing component of the IL-6 receptor. Inhibition of PI-3 kinase with wortmannin induces programmed cell death in PC-3 cells. In contrast, wortmannin has no effect on LNCaP growth when used alone; however, combined with IL-6, wortmannin promotes apoptosis in these cells. CONCLUSIONS: PI-3 kinase is involved in IL-6 signal transduction and delivers an antiapoptotic signal in human prostate cancer cell lines.
The signaling pathways involved in insulin and glucagon regulation of CYP2E1 expression were examined in primary cultured rat hepatocytes. Insulin addition to primary cultured rat hepatocytes for 24 h resulted in an approximately 80% and >90% decrease in CYP2E1 mRNA levels at 1 and 10 nM insulin, respectively, relative to untreated cells. Addition of the phosphatidylinositol 3-kinase inhibitor wortmannin, or the Src kinase inhibitor geldanamycin, prior to insulin addition, inhibited the insulin-mediated decline in CYP2E1 mRNA. In contrast, treatment of cells with glucagon (100 nM), or the cAMP analogue dibutyryl-cAMP (50 microM), for 24 h increased CYP2E1 mRNA levels by approximately 7-fold. Addition of the protein kinase A inhibitor H89 prior to glucagon treatment attenuated the glucagon-mediated increase in CYP2E1 mRNA by approximately 70%. Glucagon (100 nM) opposed the effects of insulin (1 nM) on CYP2E1 mRNA expression and conversely, insulin blocked the effects of glucagon. These data provide compelling evidence for the regulation of CYP2E1 expression via mutually antagonistic signaling pathways involving insulin and glucagon.