Department of Biochemistry and Molecular Immunology, Institute of Biochemistry and Molecular Biology, University Clinic, RWTH Aachen University, Aachen, Germany.
Cell Signal. 2011 May;23(5):866-75. doi: 10.1016/j.cellsig.2011.01.012. Epub 2011 Jan 22.
Recognition of bacterial constituents by mast cells (MCs) is dependent on the presence of pattern recognition receptors, such as Toll-like receptors (TLRs). The final cellular response, however, depends on the influence of multiple environmental factors. In the current study we tested the hypothesis that the PI3K-activating ligands insulin-like growth factor-1 (IGF-1), insulin, antigen, and Steel Factor (SF) are able to modulate the TLR4-mediated production of proinflammatory cytokines in murine MCs. Costimulation with any of these ligands caused increased LPS-triggered secretion of IL-6 and TNF-α, but attenuated the production of IL-1β, though all three cytokines were produced in an NFκB-dependent manner. The pan-specific PI3K-inhibitor Wortmannin reverted the altered production of these cytokines. In agreement, MCs deficient for SHIP1, a negative regulator of the PI3K pathway, showed augmented secretion of IL-6/TNF-α and reduced production of IL-1β in response to LPS alone. The differential effects of IGF-1 on TLR4-mediated cytokine production were also observed in the context of TLR2 and IL-33 receptor-mediated MC activation. Importantly, these effects were seen in both bone marrow-derived and peritoneal MCs, suggesting general relevance for MCs. Using pharmacological and genetic tools, we could show that the p110δ isoform of PI3K is strongly implicated in SF-triggered suppression of LPS-induced IL-1β production. Costimulation with antigen was affected to a lesser extent. In conclusion, NFκB-dependent production of proinflammatory cytokines in MCs is differentially controlled by PI3K-activating ligand/receptor systems.
肥大细胞（MCs）识别细菌成分依赖于模式识别受体，如 Toll 样受体（TLRs）的存在。然而，最终的细胞反应取决于多种环境因素的影响。在本研究中，我们测试了以下假设：PI3K 激活配体胰岛素样生长因子-1（IGF-1）、胰岛素、抗原和 Steel 因子（SF）能够调节 TLR4 介导的小鼠 MC 中促炎细胞因子的产生。用这些配体中的任何一种进行共刺激都会导致 LPS 触发的 IL-6 和 TNF-α分泌增加，但会减弱 IL-1β的产生，尽管所有这三种细胞因子都是以 NFκB 依赖的方式产生的。泛特异性 PI3K 抑制剂 Wortmannin 逆转了这些细胞因子产生的改变。与预期一致，PI3K 途径的负调节剂 SHIP1 缺失的 MCs 在单独 LPS 刺激下显示出增加的 IL-6/TNF-α分泌和减少的 IL-1β产生。IGF-1 对 TLR4 介导的细胞因子产生的不同影响也在 TLR2 和 IL-33 受体介导的 MC 激活的背景下观察到。重要的是，这些效应在骨髓衍生和腹腔 MCs 中均可见，表明对 MCs 具有普遍意义。使用药理学和遗传学工具，我们可以证明 PI3K 的 p110δ 同工型强烈参与 SF 触发的 LPS 诱导的 IL-1β 产生的抑制。抗原的共刺激受到的影响较小。总之，PI3K 激活配体/受体系统以不同的方式控制 MC 中促炎细胞因子的 NFκB 依赖性产生。
