Panettieri R A, Lazaar A L, Puré E, Albelda S M
Department of Medicine, University of Pennsylvania Medical Center, Philadelphia.
J Immunol. 1995 Mar 1;154(5):2358-65.
Asthma is a disease of airway inflammation and hyper-reactivity associated with lymphocytic infiltration in the bronchial submucosa. We recently demonstrated that human airway smooth muscle (ASM) cells express the cell adhesion molecules ICAM-1 and VCAM-1, which are up-regulated by cytokines such as TNF-alpha, and which mediate binding of activated T lymphocytes. In this study, we examined whether an increase in [cAMP]i, presumably via activation of cAMP-dependent protein kinase, modulates TNF-alpha-induced ICAM-1 and VCAM-1 on ASM. We found that treatment of ASM with either forskolin, which directly activates adenylyl cyclase, or with cholera toxin, which activates the heterotrimeric GTP-binding protein, Gs, inhibited TNF-alpha-induced cell adhesion molecule expression. In addition, treatment with either isoproterenol or prostaglandin E2, which activates receptors coupled to Gs and increases [cAMP]i, also inhibited TNF-alpha-induced expression of ICAM-1 and VCAM-1 on ASM. Furthermore, adhesion of activated T cells to TNF-alpha-stimulated ASM was inhibited by treating the ASM cells with either forskolin or PGE2. These data suggest that cAMP-dependent protein kinase activation decreases cytokine-induced expression of cell adhesion molecules on ASM cells, modulates T cell binding to airway myocytes and, thus, suggests novel therapeutic approaches to airway inflammation.
哮喘是一种气道炎症和高反应性疾病，与支气管黏膜下层的淋巴细胞浸润有关。我们最近证明，人气道平滑肌（ASM）细胞表达细胞黏附分子ICAM-1和VCAM-1，它们被TNF-α等细胞因子上调，并介导活化T淋巴细胞的结合。在本研究中，我们研究了细胞内[环磷酸腺苷（cAMP）]水平升高（可能是通过激活cAMP依赖性蛋白激酶）是否会调节TNF-α诱导的ASM细胞上ICAM-1和VCAM-1的表达。我们发现，用直接激活腺苷酸环化酶的福斯可林或激活异三聚体GTP结合蛋白Gs的霍乱毒素处理ASM细胞，可抑制TNF-α诱导的细胞黏附分子表达。此外，用异丙肾上腺素或前列腺素E2处理，它们激活与Gs偶联的受体并增加细胞内[cAMP]水平，也能抑制TNF-α诱导的ASM细胞上ICAM-1和VCAM-1的表达。此外，用福斯可林或前列腺素E2处理ASM细胞，可抑制活化T细胞与TNF-α刺激的ASM细胞的黏附。这些数据表明，cAMP依赖性蛋白激酶的激活可降低细胞因子诱导的ASM细胞上细胞黏附分子的表达，调节T细胞与气道肌细胞的结合，从而提示了气道炎症的新治疗方法。
