Elucidation of a novel signaling pathway responsible for the roles of phospholipase Cepsilon in augmentation of inflammation and carcinogenesis

我们研究了磷脂酶C肽（PLC肽），小GTP酶Ras和Rap的效应器，以及其在整个动物中的功能，炎症增强的分子机制。我们发现，PLC通过促进肿瘤坏死因子（TNF）-α刺激细胞后转录因子NF-κ B的核转位，在诱导促炎细胞因子表达中发挥作用。鉴定了内源性配体的候选物，其从TNF-α刺激的细胞分泌并以自分泌方式诱导PLC ε依赖性细胞因子表达。此外，我们确定了一种蛋白激酶，其以PLC ε依赖性方式激活，并可能参与细胞因子表达的诱导。此外，通过对PLC 19基因敲除小鼠的研究，我们阐明了PLC 19在结肠炎诱导的肠道癌变和支气管哮喘发病机制中的重要作用。

We investigated the molecular mechanisms underlying the augmentation of inflammation by phospholipase Cepsilon (PLCepsilon), an effector of the small GTPases Ras and Rap, as well as its function in whole animals. We found that PLCepsilon plays a role in induction of the proinflammatory cytokine expression by facilitating the nuclear translocation of the transcription factor NF-kappaB upon stimulation of cells with tumor necrosis factor (TNF)-alpha. A candidate of the endogenous ligand was identified that is secreted from TNF-alpha-stimulated cells and induces the PLCepsilon-dependent cytokine expression in an autocrine manner. Moreover, we identified a protein kinase which is activated in a PLCepsilon-dependent manner and presumably involved in the induction of the cytokine expression. Furthermore, from the studies using PLCepsilon knockout mice, we clarified the crucial roles of PLCepsilon in the colitis-induced intestinal carcinogenesis and the pathogenesis of bronchial asthma.