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首页> 外文会议>Advances in biomedical research >Cross-Talk of Hypoxic and Map Kinase-Dependent Signalling Pathways in Toll- Like Receptor (TLR)-Mediated Inflammatory Reactions
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Cross-Talk of Hypoxic and Map Kinase-Dependent Signalling Pathways in Toll- Like Receptor (TLR)-Mediated Inflammatory Reactions

机译：在Toll样受体（TLR）介导的炎症反应中低氧和依赖于地图激酶的信号通路的交叉讨论

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TLRs are the key pattern recognition receptors that lie at the core of resistance to disease, initiating most of the phenomena that occur in the course of innate immune reactions. In our studies we found that ligand-induced TLR4 (cell membrane-associated receptor which recognises LPS of Gram-negative bacteria) signalling triggers cross-talk of ASK1 downstream pathway and HIF-1 alpha in THP-1 human myeloid cells. Both pathways were activated via redox-dependent mechanism associated with tyrosine kinase/phospholipase C-1 gamma-mediated activation of protein kinase C alpha/beta. The latter activated NADPH oxidase and, therefore, the production of ROS which up-regulate both HIF-1alpha and ASK1. ASK1 contributes to the stabilisation of HIF-1alpha protein via activation of p38 MAP kinase which directly phosphorylates HIF-1 alpha. Knockdown of HIF-1 alpha in THP-1 cells with siRNA suggested that this protein supports TLR4-dependent production of pro-inflammatory cytokines by protecting the cells against depletion of ATP and therefore against death. Ligand-induced activation of TLR7/8 (endosomal receptors which recognise viral ssRNA) leads to the accumulation of HIF-1 alpha protein in THP-1 human myeloid macrophages via redox- and reactive nitrogen species-dependent mechanisms. ASK1 and its downstream MAP kinases as well as PI3-kinase are not involved in TLR7/8-mediated HIF-1alpha accumulation. Experiments with HIF-1 alpha knockdown THP-1 cells have clearly demonstrated that this protein is important for the protection of these cells against TLR7/8-induced depletion of ATP and for production of the pro-inflammatory cytokines. Therefore membrane-associated and endosomal TLRs use differential mechanisms of activation of HIF-1 alpha but the function of the protein is similar in both cases.
机译：TLR是关键的模式识别受体，位于疾病抵抗力的核心，引发了在先天免疫反应过程中发生的大多数现象。在我们的研究中，我们发现配体诱导的TLR4（识别革兰氏阴性细菌LPS的细胞膜相关受体）信号触发了THP-1人骨髓细胞中ASK1下游途径和HIF-1 alpha的串扰。两种途径均通过与酪氨酸激酶/磷脂酶C-1γ介导的蛋白激酶Cα/β活化相关的氧化还原依赖性机制被激活。后者激活了NADPH氧化酶，因此产生了上调HIF-1α和ASK1的ROS。 ASK1通过激活直接磷酸化HIF-1 alpha的p38 MAP激酶而有助于HIF-1alpha蛋白的稳定化。用siRNA敲除THP-1细胞中的HIF-1α，表明该蛋白可通过保护细胞免于ATP消耗并因此防止死亡来支持TLR4依赖性促炎细胞因子的产生。配体诱导的TLR7 / 8（识别病毒ssRNA的内体受体）的激活导致TIF-1人类髓样巨噬细胞中HIF-1α蛋白通过氧化还原和活性氮物种依赖性机制积累。 ASK1及其下游MAP激酶以及PI3-激酶不参与TLR7 / 8介导的HIF-1alpha积累。用HIF-1α敲低THP-1细胞进行的实验清楚地表明，该蛋白对于保护这些细胞免于TLR7 / 8诱导的ATP消耗和促炎性细胞因子的产生非常重要。因此，膜相关的TLR和内体TLR使用不同的激活HIF-1α的机制，但是在两种情况下蛋白的功能是相似的。

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