Hakonarson H, Maskeri N, Carter C, Chuang S, Grunstein M M
Division of Pulmonary Medicine, Joseph Stokes, Jr. Research Institute, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
J Clin Invest. 1999 Sep;104(5):657-67. doi: 10.1172/JCI7137.
T-helper type 2 (Th2) cytokines have been implicated in the pathogenesis of the pulmonary inflammatory response and altered bronchial responsiveness in allergic asthma. To elucidate the mechanism of Th2-dependent mediation of altered airway responsiveness in the atopic asthmatic state, the expression and actions of specific cytokines were examined in isolated rabbit and human airway smooth muscle (ASM) tissues and cultured cells passively sensitized with sera from atopic asthmatic patients or nonatopic/nonasthmatic (control) subjects. Relative to control tissues, the atopic asthmatic sensitized ASM exhibited significantly enhanced maximal isometric contractility to acetylcholine and attenuated relaxation responses to isoproterenol. These proasthmatic changes in agonist responsiveness were ablated by pretreating the atopic sensitized tissues with either an IL-5 receptor blocking antibody (IL-5ra) or the human recombinant IL-1 receptor antagonist (IL-1ra), whereas an IL-4 neutralizing antibody had no effect. Moreover, relative to controls, atopic asthmatic sensitized ASM cells demonstrated an initial, early (after 3 hours of incubation) increased mRNA expression and protein release of IL-5. This was followed (after 6 hours of incubation) by an enhanced mRNA expression and release of IL-1beta protein, an effect that was inhibited in sensitized cells pretreated with IL-5ra. Extended studies demonstrated that naive ASM exposed to exogenously administered IL-5 exhibited an induced upregulated mRNA expression and protein release of IL-1beta associated with proasthmatic-like changes in ASM constrictor and relaxant responsiveness, and that these effects were ablated in tissues pretreated with IL-1ra. Taken together, these observations provide new evidence that (a) the Th2 cytokine IL-5 and the pleiotropic proinflammatory cytokine IL-1beta are endogenously released by atopic asthmatic sensitized ASM and mechanistically interact to mediate the proasthmatic perturbations in ASM responsiveness; and (b) the nature of this interaction is given by an initial endogenous release of IL-5, which then acts to induce the autologous release of IL-1beta by the sensitized ASM itself, resulting in its autocrine manifestation of the proasthmatic phenotype.
2型辅助性T细胞（Th2）细胞因子与过敏性哮喘中肺部炎症反应的发病机制及支气管反应性改变有关。为了阐明特应性哮喘状态下Th2依赖性介导气道反应性改变的机制，我们检测了用特应性哮喘患者或非特应性/非哮喘（对照）受试者血清被动致敏的分离兔和人气道平滑肌（ASM）组织及培养细胞中特定细胞因子的表达和作用。与对照组织相比，特应性哮喘致敏的ASM对乙酰胆碱的最大等长收缩力显著增强，对异丙肾上腺素的舒张反应减弱。用IL-5受体阻断抗体（IL-5ra）或人重组IL-1受体拮抗剂（IL-1ra）预处理特应性致敏组织可消除激动剂反应性的这些促哮喘变化，而IL-4中和抗体则无作用。此外，与对照相比，特应性哮喘致敏的ASM细胞在孵育3小时后最初表现出IL-5的mRNA表达和蛋白释放增加。随后（孵育6小时后）IL-1β蛋白的mRNA表达和释放增强，在用IL-5ra预处理的致敏细胞中这种作用受到抑制。进一步的研究表明，暴露于外源性IL-5的未致敏ASM表现出IL-1β的mRNA表达上调和蛋白释放增加，同时ASM收缩和舒张反应性出现类似促哮喘的变化，在用IL-1ra预处理的组织中这些作用被消除。综上所述，这些观察结果提供了新的证据，即（a）Th2细胞因子IL-5和多效性促炎细胞因子IL-1β由特应性哮喘致敏的ASM内源性释放，并通过机制相互作用介导ASM反应性的促哮喘扰动；（b）这种相互作用的本质是由IL-5的内源性释放开始，然后它作用于诱导致敏的ASM自身释放IL-1β，导致其促哮喘表型的自分泌表现。
