Functional coupling between secretory and cytosolic phospholipase A2 modulates tumor necrosis factor-α- and interleukin-1β-induced NF-κB activation
Functional coupling between secretory and cytosolic phospholipase A2 modulates tumor necrosis factor-α- and interleukin-1β-induced NF-κB activation
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DOI：
10.1074/jbc.m008481200
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发表时间：
2001-08-10
影响因子：
4.8
通讯作者：
Johansen, B
中科院分区：
文献类型：
--
作者：
Anthonsen, MW;Solhaug, A;Johansen, B
肿瘤坏死因子(TNF)- α和白细胞介素(IL)-1 β是转录因子NF-kappaB的有效激活因子，在炎症条件下诱导。我们之前已经证明分泌和胞质磷脂酶A(2) （PLA(2)）都参与了tnf - α和IL-1 β诱导的NF-kappaB激活。在这项研究中，我们研究了PLA的作用机制，涉及下游花生四烯酸（AA）代谢物，以及PLA(2)介导NF-kappaB活化之间的功能偶联。我们发现，除了分泌性和胞质性PLA2s抑制剂外，5-脂氧合酶抑制剂还能减弱tnf - α和IL-1 β刺激的NF-KB激活。外源性添加白三烯B-4 （LTB4）恢复了被5-脂氧合酶抑制剂或LTB4受体拮抗剂降低的NF-kappaB激活，从而确定LTB4是NF-kappaB信号传导的中介。tnf - α -和IL-1 β诱导的AA从细胞膜释放伴随着胞浆PLA的磷酸化(2)。分泌PLA(2)和5-脂氧合酶/LTB4功能抑制剂显著降低AA释放，几乎完全消除细胞质PLA2磷酸化。这表明通过5-脂氧合酶代谢物分泌的PLA(2)是细胞质内PLA2和AA释放的重要上游调节剂。因此，我们的研究结果表明，在细胞因子激活的角质形成细胞中，分泌和胞质PLA2之间存在功能联系，这为分泌和胞质PLA2参与花生四烯酸信号传导和NF-KB激活以响应促炎细胞因子提供了分子解释。
Tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 beta are potent activators of the transcription factor NF-kappaB, induced during inflammatory conditions. We have previously shown that both secretory and cytosolic phospholipase A(2) (PLA(2)) are involved in TNF-alpha- and IL-1 beta -induced NF-kappaB activation. In this study, we have addressed the mechanism of PLA, involvement with respect to downstream arachidonic acid (AA) metabolites and the functional coupling between PLA(2)s mediating NF-kappaB activation. We show that in addition to inhibitors of secretory and cytosolic PLA2s, 5-lipoxygenase inhibitors attenuate TNF-alpha- and IL-1 beta -stimulated NF-KB activation. Exogenous addition of leukotriene B-4 (LTB4) restored NF-kappaB activation reduced by 5-lipoxygenase inhibitors or an LTB4 receptor antagonist, thus identifying LTB4 as a mediator in signaling to NF-kappaB. TNF-alpha- and IL-1 beta -induced AA release from cellular membranes was accompanied by phosphorylation of cytosolic PLA(2). Inhibitors of secretory PLA(2) and of 5-lipoxygenase/LTB4 functionality markedly reduced AA release and nearly completely abolished cytosolic PLA2 phosphorylation. This demonstrates that secretory PLA(2) through 5-lipoxygenase metabolites, is an essential upstream regulator of cytosolic PLA2 and AA release. Our results therefore suggest the existence of a functional link between secretory and cytosolic PLA2 in cytokine-activated keratinocytes, providing a molecular explanation for the participation of both secretory and cytosolic PLA(2) in arachidonic acid signaling and NF-KB activation in response to proinflammatory cytokines.