Hundley Thomas R, Gilfillan Alasdair M, Tkaczyk Christine, Andrade Marcus V, Metcalfe Dean D, Beaven Michael A
National Institutes of Health, Bethesda, MD 20892-1760, USA.
Blood. 2004 Oct 15;104(8):2410-7. doi: 10.1182/blood-2004-02-0631. Epub 2004 Jun 24.
In human mast cells, derived from CD34(+) peripheral blood cells, we observed that Kit ligand (KL) failed to induce degranulation but acted in synergy with antigen to markedly enhance degranulation, levels of cytokine gene transcripts, and production of cytokines. Further examination revealed that antigen and KL activated common and unique signaling pathways to account for these varied responses. KL, unlike antigen, failed to activate protein kinase C but activated phospholipase Cgamma and calcium mobilization and augmented these signals as well as degranulation when added together with antigen. Both KL and antigen induced signals that are associated with cytokine production, namely phosphorylation of the mitogen-activated protein kinases, phosphatidylinositol 3-kinase-dependent phosphorylation of protein kinase B (also known as Akt), and phosphorylation of nuclear factor kappaB (NFkappaB). However, only KL stimulated phosphorylation of signal transducer and activator of transcription 5 (STAT5) and STAT6, whereas antigen weakly stimulated the protein kinase C-dependent induction and phosphorylation of c-Jun and associated activating protein-1 (AP-1) components, an action that was markedly potentiated by costimulation with KL. Interestingly, most signals were down-regulated on continuous exposure to KL but were reactivated along with cytokine gene transcription on addition of antigen. The findings, in total, indicated that a combination of FcepsilonRI and Kit-mediated signals and transcriptional processes were required for optimal physiologic responses of human mast cells to antigen.
在源自CD34(+)外周血细胞的人肥大细胞中，我们观察到，Kit配体（KL）未能诱导脱颗粒，但可与抗原协同作用，显著增强脱颗粒、细胞因子基因转录水平及细胞因子的产生。进一步研究发现，抗原和KL激活了共同及独特的信号通路，以解释这些不同的反应。与抗原不同，KL未能激活蛋白激酶C，但激活了磷脂酶Cγ和钙动员，并在与抗原一起添加时增强了这些信号以及脱颗粒。KL和抗原均诱导了与细胞因子产生相关的信号，即丝裂原活化蛋白激酶的磷酸化、蛋白激酶B（也称为Akt）的磷脂酰肌醇3激酶依赖性磷酸化以及核因子κB（NFκB）的磷酸化。然而，只有KL刺激信号转导和转录激活因子5（STAT5）和STAT6的磷酸化，而抗原微弱地刺激蛋白激酶C依赖性的c-Jun及相关激活蛋白-1（AP-1）成分的诱导和磷酸化，这种作用在与KL共刺激时显著增强。有趣的是，大多数信号在持续暴露于KL时被下调，但在添加抗原时与细胞因子基因转录一起重新激活。总体而言，这些发现表明，FcepsilonRI和Kit介导的信号以及转录过程的组合是人类肥大细胞对抗原产生最佳生理反应所必需的。
