Protein kinase Cε IS required for the induction of mitogen-activated protein kinase phosphatase-1 in lipopolysaccharide-stimulated macrophages
Protein kinase Cε IS required for the induction of mitogen-activated protein kinase phosphatase-1 in lipopolysaccharide-stimulated macrophages
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DOI：
10.4049/jimmunol.164.1.29
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发表时间：
2000-01-01
影响因子：
4.4
通讯作者：
Celada, A
中科院分区：
文献类型：
--
作者：
Valledor, AF;Xaus, J;Celada, A
LPS诱导骨髓巨噬细胞瞬时表达丝裂原活化蛋白激酶（MAPK）磷酸酶-1 （MKP-1）。由于MKP-1在不同MAPK级联的衰减中起着至关重要的作用，我们对lps刺激的巨噬细胞中参与控制MKP-1表达的信号机制的表征感兴趣，MKP-1的诱导被酪氨酸激酶抑制剂金木黄酮和两种不同的蛋白激酶C （PKC）抑制剂（GF109203X和calphostin C）阻断。我们之前已经证明骨髓巨噬细胞表达PKC β I， epsilon和zeta亚型。在所有这些中，只有PKC β I和epsilon被GF109203X抑制，以下论据表明PKC epsilon是LPS诱导MKP-1的选择性必需的，首先，在长期暴露于PMA处理的巨噬细胞中，LPS诱导MKP-1与PKC epsilon的表达水平相关，而与PKC β I的表达水平无关，其次，Go6976，一种选择性的常规PKCs，包括PKC β I的抑制剂，不会改变LPS诱导MKP-1。在巨噬细胞对LPS的反应过程中，阻断PKC epsilon表达的反义寡核苷酸抑制了MKP-1的诱导，并导致细胞外信号调节激酶活性的增加。最后，在LPS刺激的巨噬细胞中，我们观察到PKC epsilon的显著激活。我们的研究结果证明了PKC epsilon在巨噬细胞中诱导MKP-1和随后的MAPK活性阴性控制中的重要作用。
LPS induces in bone marrow macrophages the transient expression of mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1). Because MKP-1 plays a crucial role in the attenuation of different MAPK cascades, we were interested in the characterization of the signaling mechanisms involved in the control of MKP-1 expression in LPS-stimulated macrophages, The induction of MKP-1 was blocked by genistein, a tyrosine kinase inhibitor, and by two different protein kinase C (PKC) inhibitors (GF109203X and calphostin C), We had previously shown that bone marrow macrophages express the isoforms PKC beta I, epsilon, and zeta. Of all these, only PKC beta I and epsilon are inhibited by GF109203X, The following arguments suggest that PKC epsilon is required selectively for the induction of MKP-1 by LPS, First, in macrophages exposed to prolonged treatment with PMA, MKP-1 induction by LPS correlates with the levels of expression of PKC epsilon but not with that of PKC beta I, Second, Go6976, an inhibitor selective for conventional PKCs, including PKC beta I, does not alter MKP-1 induction by LPS, Last, antisense oligonucleotides that block the expression of PKC epsilon, but not those selective for PKC beta I or PKC zeta, inhibit MKP-1 induction and lead to an increase of extracellular-signal regulated kinase activity during the macrophage response to LPS, Finally, in macrophages stimulated with LPS we observed significant activation of PKC epsilon, In conclusion, our results demonstrate an important role for PKC epsilon in the induction of MKP-1 and the subsequent negative control of MAPK activity in macrophages.