Hemozoin induces macrophage chemokine expression through oxidative stress-dependent and -independent mechanisms
Hemozoin induces macrophage chemokine expression through oxidative stress-dependent and -independent mechanisms
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DOI：
10.4049/jimmunol.174.1.475
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发表时间：
2005-01-01
影响因子：
4.4
通讯作者：
Olivier, M
中科院分区：
文献类型：
--
作者：
Jaramillo, M;Godbout, M;Olivier, M
趋化因子的产生与疟疾相关的免疫病理学有关。以前的研究表明，疟原虫色素（HZ），寄生虫代谢产物释放过程中，可能是一个重要的来源，这些促炎介质。在这项研究中，我们研究了HZ诱导的巨噬细胞（MO）趋化因子mRNA表达的分子机制。我们发现恶性疟原虫HZ和合成HZ都增加了小鼠BIOR Mphi中各种趋化因子转录本（MIP-1 alpha/CCL 3、MIP-1、beta/CCL 4、MIP-2/CXCL 2和MCP-1/CCL 2）的mRNA水平。对HZ的细胞反应涉及ERKI/2磷酸化、NF-κ B活化、活性氧（ROS）产生和ROS依赖性蛋白酪氨酸磷酸酶下调。选择性抑制IkappaB α或ERK 1/2通路可消除NF-κ B活化和趋化因子上调。类似地，用超氧化物歧化酶阻断HZ诱导的Mphi ROS抑制趋化因子诱导，强烈降低NF-κ B活化，并恢复HZ介导的Mphi蛋白酪氨酸磷酸酶失活。与此相反，超氧化物歧化酶对HZ磷酸化EKR 1/2没有影响。总的来说，这些数据表明，HZ触发ROS依赖性和非依赖性信号，导致Mphi中趋化因子mRNA表达增加。总的来说，我们的研究结果可能有助于更好地了解寄生虫成分（如HZ）在疟疾感染期间调节免疫反应的分子机制。
Chemokine production has been associated with the immunopathology related to malaria. Previous findings indicated that hemozoin (HZ), a parasite metabolite released during schizogeny, might be an important source of these proinflammatory mediators. In this study we investigated the molecular mechanisms underlying HZ-inducible macrophage (MO) chemokine mRNA expression. We found that both Plasmodium falciparum HZ and synthetic HZ increase mRNA levels of various chemokine transcripts (MIP-1alpha/CCL3, MIP-1,beta/CCL4, MIP-2/CXCL2, and MCP-1/CCL2) in murine BIOR Mphi. The cellular response to HZ involved ERKI/2 phosphorylation, NF-kappaB activation, reactive oxygen species (ROS) generation, and ROS-dependent protein-tyrosine phosphatase down-regulation. Selective inhibition of either IkappaBalpha or the ERK1/2 pathway abolished both NF-kappaB activation and chemokine up-regulation. Similarly, blockage of HZ-inducible Mphi ROS with superoxide dismatase suppressed chemokine induction, strongly reduced NF-kappaB activation, and restored HZ-mediated Mphi protein-tyrosine phosphatase inactivation. In contrast, superoxide dismutase had no effect on EKR1/2 phosphorylation by HZ. Collectively, these data indicate that HZ triggers ROS-dependent and -independent signals, leading to increased chemokine mRNA expression in Mphi. Overall, our findings may help to better understand the molecular mechanisms through which parasite components, such as HZ, modulate the immune response during malaria infection.