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Query: UMLS:C0338671 (Steroids)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Steroids have been shown to inhibit the function of fresh or IL-2-activated natural killer (NK) cells. Since IL-15 plays a key role in NK-cell development and function, we comparatively analyzed the effects of methylprednisolone on IL-2- or IL-15-cultured NK cells. Methylprednisolone inhibited the surface expression of the major activating receptors NKp30 and NKp44 in both conditions, whereas NK-cell proliferation and survival were sharply impaired only in IL-2-cultured NK cells. Accordingly, methylprednisolone inhibited Tyr phosphorylation of STAT1, STAT3, and STAT5 in IL-2-cultured NK cells but only marginally in IL-15-cultured NK cells, whereas JAK3 was inhibited under both conditions. Also, the NK cytotoxicity was similarly impaired in IL-2- or IL-15-cultured NK cells. This effect strictly correlated with the inhibition of ERK1/2 Tyr phosphorylation, perforin release, and cytotoxicity in a redirected killing assay against the FcRgamma(+) P815 target cells upon cross-linking of NKp46, NKG2D, or 2B4 receptors. In contrast, in the case of CD16, inhibition of ERK1/2 Tyr phosphorylation, perforin release, and cytotoxicity were not impaired. Our study suggests a different ability of IL-15-cultured NK cells to survive to steroid treatment, thus offering interesting clues for a correct NK-cell cytokine conditioning in adoptive immunotherapy.
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PMID:Molecular analysis of the methylprednisolone-mediated inhibition of NK-cell function: evidence for different susceptibility of IL-2- versus IL-15-activated NK cells. 1723 44

Both steroids and growth factors stimulate proliferation of steroid-dependent tumor cells, and interaction between these signaling pathways occurs at several levels. Steroid receptors are classified as ligand-activated transcription factors, and steps by which they activate target gene transcription are well understood. Several steroid responses have now been functionally linked to other intracellular signaling pathways, including c-Src or tyrosine kinase receptors. Steroids such as 17beta-estradiol (E2), via binding to cytoplasmic or membrane-associated receptors, were also shown to rapidly activate intracellular signaling cascades such as ERK, PI3K and STATs. These E2-stimulated phosphorylations can then contribute to altered tumor cell function. ER-positive breast cancer cells, in which proliferation is stimulated by E2 and suppressed by antiestrogens, have been of particular interest in dissecting nuclear and cytoplasmic roles of estrogen receptors (ER). In some cell contexts, ER interacts directly with the intracellular tyrosine kinase c-Src and other cytoplasmic signaling and adaptor molecules, such as Shc, PI3K, MNAR, and p130 Cas. Although the hierarchy among these associations is not known, it is clear that c-Src plays a fundamental role in both growth factor and E2-stimulated cell growth, and this may also require other growth factor receptors such as those for EGF or IGF-1. STAT transcription factors represent one pathway to integrate E2 cytoplasmic and nuclear signaling. STAT5 is phosphorylated in the cytoplasm at an activating tyrosine in response to E2 or EGF, and then is translocated to the nucleus to stimulate target gene transcription. E2 stimulates recruitment of STAT5 and ER to the promoter of several proliferative genes, and STAT5 knockdown prevents recruitment of either protein to these promoters. STAT5 activation by E2 in breast cancer cells requires c-Src and EGF receptor, and inhibition of c-Src or EGFR, or knockdown of STAT5, prevents E2 stimulation of several genes and breast cancer cell proliferation. Hyperactivation of the growth factor receptor-c-Src pathway can in some contexts decrease growth responses to E2, or render cells and tumors resistant to suppressive actions of endocrine therapies. Crosstalk between growth factors and steroids in both the cytoplasm and nucleus may thus have a profound impact on complex biological processes such as cell growth, and may play a significant role in the treatment of steroid-dependent breast cancers.
Steroids 2009 Jul
PMID:Novel actions of estrogen to promote proliferation: integration of cytoplasmic and nuclear pathways. 1899 36