Pulmonary surfactant protein a regulates TLR expression and activity in human macrophages
Pulmonary surfactant protein a regulates TLR expression and activity in human macrophages
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DOI：
10.4049/jimmunol.180.12.7847
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发表时间：
2008-06-15
影响因子：
4.4
通讯作者：
Schlesinger, Larry S.
中科院分区：
文献类型：
--
作者：
Henning, Lisa N.;Azad, Abul K.;Schlesinger, Larry S.
肺部的先天免疫系统对空气中的各种微生物做出反应。尽管它的特异性是广泛的，并且基于对病原体相关分子模式的识别，但它是唯一被调节来限制炎症从而防止气体交换的肺泡受损的。巨噬细胞是该系统的关键细胞决定因素，通过TLRs等模式识别受体识别微生物，TLRs通常介导促炎反应。肺集素，表面活性蛋白A(SP-A)，已成为调节微生物-巨噬细胞在这种环境中相互作用的重要先天免疫决定因素。在这项研究中，我们报道了在原代人单核细胞向巨噬细胞分化过程中，基础和SP-A诱导的TLR2和TLR4表达的转录和翻译后调节。尽管SP-A能够上调人巨噬细胞上TLR2的表达，但它抑制了这些细胞中的TLR2和TLR4信号。SP-A减少了核因子-kappa B活性的关键调节因子I-kappa Bα的磷酸化，以及p65的核转位，从而导致TLR配体引起的肿瘤坏死因子-α的分泌减少。SP-A还减少了包括MAPK家族成员在内的NF-kappa B上游TLR信号蛋白的磷酸化。最后，我们首次报道了SP-A降低了Akt的磷酸化，Akt是核因子-kappa B和潜在的MAPKs的主要细胞调节因子。这些数据表明，SP-A通过调节巨噬细胞TLR活性，在调节肺部炎症反应中发挥关键作用。
The pulmonary innate immune system responds to various airborne microbes. Although its specificity is broad and based on the recognition of pathogen-associated molecular patterns, it is uniquely regulated to limit inflammation and thereby prevent damage to the gas-exchanging alveoli. Macrophages, critical cell determinants of this system, recognize microbes through pattern recognition receptors such as TLRs, which typically mediate proinflammatory responses. The lung collectin, surfactant protein A (SP-A), has emerged as an important innate immune determinant that regulates microbe-macrophage interactions in this environment. In this study, we report the basal and SP-A-induced transcriptional and posttranslational regulation of TLR2 and TLR4 expression during the differentiation of primary human monocytes into macrophages. Despite SP-A's ability to up-regulate TLR2 expression on human macrophages, it dampens TLR2 and TLR4 signaling in these cells. SP-A decreases the phosphorylation of I kappa B alpha, a key regulator of NF-kappa B activity, and nuclear translocation of p65 which result in diminished TNF-alpha secretion in response to TLR ligands. SP-A also reduces the phosphorylation of TLR signaling proteins upstream of NF-kappa B, including members of the MAPK family. Finally, we report for the first time that SP-A decreases the phosphorylation of Akt, a major cell regulator of NF-kappa B and potentially MAPKs. These data identify a critical role for SP-A in modulating the lung inflammatory response by regulating macrophage TLR activity.