Activation of cytokine production by secreted phospholipase A2 in human lung macrophages expressing the M-type receptor
Activation of cytokine production by secreted phospholipase A2 in human lung macrophages expressing the M-type receptor
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DOI：
10.4049/jimmunol.174.1.464
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发表时间：
2005-01-01
影响因子：
4.4
通讯作者：
Triggiani, M
中科院分区：
文献类型：
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作者：
Granata, F;Petraroli, A;Triggiani, M
分泌性磷脂酶A(2) （sPLA(2)）是炎症性疾病期间在血浆和细胞外液中释放的酶。由于人组IB和X sPLA(2)s在肺中表达，我们研究了它们对原代人肺巨噬细胞（HLM）的影响。sPLA(2)s通过增加tnf - α和IL-6 mRNA的表达，以浓度依赖性的方式诱导其释放。这种作用与它们的酶活性无关，因为1)sPLA(2)s从HLM中动员花生四烯酸的能力与它们诱导细胞因子产生的能力无关；2) IB组sPLA(2)的两个催化失活异构体(溴苯酰溴失活的人sPLA（2)和猪sPLA的H48Q突变体(2)）在诱导细胞因子产生方面与具有催化活性的sPLA(2)S一样有效。通过RT-PCR、免疫印迹、免疫沉淀和流式细胞术检测，HLM在mRNA和蛋白水平上表达sPLA(2)s的m型受体。meindoxam降低sPLA(2)活性以及与m型受体的结合，抑制sPLA(2)诱导的细胞因子的产生。与sPLA(2)S一起培养的HLM与ERK1/2的磷酸化有关，该途径的特异性抑制剂PD98059显著降低了sPLA(2)S诱导的IL-6的产生。总之，人肺中产生的两种不同的sPLA(2)S通过一种独立于酶活性的机制刺激HLM产生细胞因子，该机制涉及ERK1/2途径的激活。HLM表达m型受体，但其在诱导细胞因子产生中的作用有待进一步研究。
Secreted phospholipases A(2) (sPLA(2)) are enzymes released in plasma and extracellular fluids during inflammatory diseases. Because human group IB and X sPLA(2)s are expressed in the lung, we examined their effects on primary human lung macrophages (HLM). Both sPLA(2)s induced TNF-alpha and IL-6 release in a concentration-dependent manner by increasing their mRNA expression. This effect was independent of their enzymatic activity because 1) the capacity of sPLA(2)s to mobilize arachidonic acid from HLM was unrelated to their ability to induce cytokine production; and 2) two catalytically inactive isoforms of group IB sPLA(2) (bromophenacyl bromide-inactivated human sPLA(2) and the H48Q mutant of the porcine sPLA(2)) were as effective as the catalytically active sPLA(2)S in inducing cytokine production. HLM expressed the M-type receptor for sPLA(2)s at both mRNA and protein levels, as determined by RT-PCR, immunoblotting, immunoprecipitation, and flow cytometry. Me-indoxam, which decreases sPLA(2) activity as well as binding to the M-type receptor, suppressed sPLA(2)-induced cytokine production. Incubation of HLM with the sPLA(2)S was associated with phosphorylation of ERK1/2, and a specific inhibitor of this pathway, PD98059, significantly reduced the production of IL-6 elicited by sPLA(2)s In conclusion, two distinct sPLA(2)S produced in the human lung stimulate cytokine production by HLM via a mechanism that is independent of their enzymatic activity and involves activation of the ERK1/2 pathway. HLM express the M-type receptor, but its involvement in eliciting cytokine production deserves further investigation.