Human type II pneumocyte chemotactic responses to CXCR3 activation are mediated by splice variant A
Human type II pneumocyte chemotactic responses to CXCR3 activation are mediated by splice variant A
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DOI：
10.1152/ajplung.00388.2007
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发表时间：
2008-06-01
影响因子：
4.9
通讯作者：
Kelsen, Steven G.
中科院分区：
文献类型：
--
作者：
Ji, Rong;Lee, Clement M.;Kelsen, Steven G.
趋化因子受体控制造血细胞和结构细胞中的几个基本细胞过程，包括定向细胞运动，即趋化性、细胞分化和增殖。我们之前已经证明，CXCR3（肺中存在的 Th1/Tc1 炎症细胞表达的趋化因子受体）也由人气道上皮细胞表达。在气道上皮细胞中，CXCR3 的激活会诱导气道上皮细胞运动和增殖，这是肺修复的基础。本研究检测了 CXCR3 在人肺泡 II 型肺细胞中的表达和功能，其破坏导致肺气肿。通过免疫细胞化学、免疫组织化学和蛋白质印迹评估，CXCR3 存在于人类胎儿和成人 II 型肺细胞中。 CXCR3-A和-B剪接变体mRNA组成型地存在于培养的II型细胞中，但CXCR3-B的水平大大超过CXCR3-A mRNA。在培养的 II 型细胞中，I-TAC、IP-10 和 Mig 诱导趋化性。 A549 肺细胞系中 CXCR3-A 的过度表达对 I-TAC 和 IP-10 产生强烈的趋化反应。相反，I-TAC 不会在 CXCR3-B 和模拟转染细胞中诱导趋化反应。最后，I-TAC 仅在 CXCR3-A 转染的细胞中增加胞质 Ca2+ 并激活细胞外信号调节激酶、p38 和磷脂酰肌醇 3-激酶（PI 3-激酶）/蛋白激酶 B 激酶。这些数据表明CXCR3受体由人II型肺细胞表达，CXCR3-A剪接变体可能通过Ca2+激活丝裂原激活蛋白激酶和PI 3激酶信号通路介导趋化反应。 CXCR3 在肺泡上皮细胞中的表达可能对于肺细胞损伤修复很重要。
Chemokine receptors control several fundamental cellular processes in both hematopoietic and structural cells, including directed cell movement, i.e., chemotaxis, cell differentiation, and proliferation. We have previously demonstrated that CXCR3, the chemokine receptor expressed by Th1/Tc1 inflammatory cells present in the lung, is also expressed by human airway epithelial cells. In airway epithelial cells, activation of CXCR3 induces airway epithelial cell movement and proliferation, processes that underlie lung repair. The present study examined the expression and function of CXCR3 in human alveolar type II pneumocytes, whose destruction causes emphysema. CXCR3 was present in human fetal and adult type II pneumocytes as assessed by immunocytochemistry, immunohistochemistry, and Western blotting. CXCR3-A and -B splice variant mRNA was present constitutively in cultured type II cells, but levels of CXCR3-B greatly exceeded CXCR3-A mRNA. In cultured type II cells, I-TAC, IP-10, and Mig induced chemotaxis. Overexpression of CXCR3-A in the A549 pneumocyte cell line produced robust chemotactic responses to I-TAC and IP-10. In contrast, I-TAC did not induce chemotactic responses in CXCR3-B and mock-transfected cells. Finally, I-TAC increased cytosolic Ca2+ and activated the extracellular signal-regulated kinase, p38, and phosphatidylinositol 3-kinase (PI 3-kinase)/protein kinase B kinases only in CXCR3-A-transfected cells. These data indicate that the CXCR3 receptor is expressed by human type II pneumocytes, and the CXCR3-A splice variant mediates chemotactic responses possibly through Ca2+ activation of both mitogen-activated protein kinase and PI 3-kinase signaling pathways. Expression of CXCR3 in alveolar epithelial cells may be important in pneumocyte repair from injury.