Molecular analysis of the methylprednisolone-mediated inhibition of NK-cell function: evidence for different susceptibility of IL-2- versus IL-15-activated NK cells
Molecular analysis of the methylprednisolone-mediated inhibition of NK-cell function: evidence for different susceptibility of IL-2- versus IL-15-activated NK cells
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DOI：
10.1182/blood-2006-07-037846
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发表时间：
2007-05-01
期刊：
影响因子：
20.3
通讯作者：
Mingari, Maria Cristina
中科院分区：
文献类型：
--
作者：
Chiossone, Laura;Vitale, Chiara;Mingari, Maria Cristina
类固醇已被证明可以抑制新鲜或il -2激活的自然杀伤细胞（NK）的功能。由于IL-15在NK细胞的发育和功能中起着关键作用，我们比较分析了甲基强的松龙对IL-2和IL-15培养的NK细胞的影响。在这两种情况下，甲基强的松龙抑制了主要激活受体NKp30和NKp44的表面表达，而NK细胞的增殖和存活仅在il -2培养的NK细胞中受到严重损害。因此，甲基强的松龙在il -2培养的NK细胞中抑制STAT1、STAT3和STAT5的Tyr磷酸化，但在il -15培养的NK细胞中仅轻微抑制，而JAK3在两种条件下均被抑制。此外，在IL-2或il -15培养的NK细胞中，NK细胞毒性也同样受损。在NKp46、NKG2D或2B4受体交联后，对FcR γ (+) P815靶细胞的重定向杀伤实验中，这种效应与ERK1/2 Tyr磷酸化、穿孔素释放和细胞毒性的抑制密切相关。相反，在CD16的情况下，ERK1/2 tyrr磷酸化的抑制、穿孔素释放和细胞毒性均未受损。我们的研究表明，il -15培养的NK细胞对类固醇治疗的生存能力不同，从而为过继免疫治疗中正确的NK细胞细胞因子调节提供了有趣的线索。(C) 2007年由美国血液病学会出版。
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 FcR gamma(+) 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. (C) 2007 by The American Society of Hematology.