Park Jong-Hwan, Kim Yun-Gi, Shaw Michael, Kanneganti Thirumala-Devi, Fujimoto Yukari, Fukase Koichi, Inohara Naohiro, Núñez Gabriel
Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA.
J Immunol. 2007 Jul 1;179(1):514-21. doi: 10.4049/jimmunol.179.1.514.
Mesothelial cells that line the serous cavities and outer surface of internal organs are involved in inflammatory responses induced by microbial stimuli and bacterial infection. Upon exposure to bacterial products, mesothelial cells secrete chemokines, but the signaling pathways by which these cells recognize bacteria to mediate innate immune responses remain largely unknown. We report that stimulation of primary peritoneal mesothelial cells via nucleotide-binding oligomerization domain (Nod)1, a member of the intracytoplasmic Nod-like receptor family, induced potent secretion of the chemokines CXCL1 and CCL2 as well as expression of inducible NO synthase and such responses required the kinase RICK. Mesothelial cells also produced chemokines in response to TLR2, TLR3, TLR4, and TLR5 agonists, but unlike that induced by Nod1 stimulation, the TLR-mediated responses were independent of RICK. Yet, Nod1 stimulation of mesothelial cells via RICK enhanced chemokine secretion induced by LPS or IFN-gamma and cooperated with IFN-gamma in the production of NO. The i.p. administration of KF1B, a synthetic Nod1 agonist, elicited chemokine production in the serum and peritoneal fluid as well as the recruitment of neutrophils into the peritoneal cavity of wild-type mice, but not RICK-deficient mice. Finally, infection of mesothelial cells with Listeria monocytogenes induced production of CXCL1 and this response was significantly reduced in Nod1- or RICK-deficient cells. These results define mesothelial cells as microbial sensors through TLRs and Nod-like receptors and identify Nod1 and RICK as important mediators of chemokine and antimicrobial responses in mesothelial cells.
衬于浆膜腔和内脏器官外表面的间皮细胞参与由微生物刺激和细菌感染诱导的炎症反应。暴露于细菌产物时，间皮细胞会分泌趋化因子，但这些细胞识别细菌以介导先天性免疫反应的信号通路仍 largely 未知。我们报告称，通过核苷酸结合寡聚化结构域（Nod）1（一种胞质内 Nod 样受体家族成员）刺激原代腹膜间皮细胞，可诱导趋化因子 CXCL1 和 CCL2 的强效分泌以及诱导型一氧化氮合酶的表达，且此类反应需要激酶 RICK。间皮细胞也会对 TLR2、TLR3、TLR4 和 TLR5 激动剂产生趋化因子，但与 Nod1 刺激诱导的反应不同，TLR 介导的反应不依赖于 RICK。然而，通过 RICK 对间皮细胞进行 Nod1 刺激可增强 LPS 或 IFN-γ诱导的趋化因子分泌，并在 NO 的产生中与 IFN-γ协同作用。腹腔注射合成 Nod1 激动剂 KF1B 可在野生型小鼠而非 RICK 缺陷型小鼠的血清和腹腔液中引发趋化因子产生，并使中性粒细胞募集到腹腔中。最后，用单核细胞增生李斯特菌感染间皮细胞可诱导 CXCL1 的产生，而在 Nod1 或 RICK 缺陷型细胞中这种反应显著降低。这些结果将间皮细胞定义为通过 TLR 和 Nod 样受体的微生物传感器，并确定 Nod1 和 RICK 是间皮细胞中趋化因子和抗菌反应的重要介质。
