Autocrine interaction between IL-5 and IL-1β mediates altered responsiveness of atopic asthmatic sensitized airway smooth muscle
Autocrine interaction between IL-5 and IL-1β mediates altered responsiveness of atopic asthmatic sensitized airway smooth muscle
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DOI：
10.1172/jci7137
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发表时间：
1999-09-01
影响因子：
15.9
通讯作者：
Grunstein, MM
中科院分区：
文献类型：
--
作者：
Hakonarson, H;Maskeri, N;Grunstein, MM
辅助性T细胞2型（Th 2）细胞因子与过敏性哮喘的肺部炎症反应和支气管反应性改变的发病机制有关。为了阐明特应性哮喘状态下气道反应性改变的Th 2依赖性介导机制，在离体兔和人气道平滑肌（ASM）组织和培养细胞中检测特异性细胞因子的表达和作用，所述细胞因子用来自特应性哮喘患者或非特应性/非哮喘（对照）受试者的血清被动致敏。相对于对照组织，过敏性哮喘致敏的ASM表现出显着增强的最大等长收缩乙酰胆碱和衰减的舒张反应异丙肾上腺素。这些促哮喘的激动剂反应性的变化被消融预处理过敏性组织与IL-5受体阻断抗体（IL-5 ra）或人重组IL-1受体拮抗剂（IL-1 ra），而IL-4中和抗体没有效果。此外，相对于对照，特应性哮喘致敏的ASM细胞表现出初始的，早期（孵育3小时后）增加的IL-5的mRNA表达和蛋白质释放。随后（孵育6小时后）mRNA表达和IL-1 β蛋白释放增强，这种效应在用IL-5 ra预处理的致敏细胞中受到抑制。进一步的研究表明，暴露于外源性IL-5的幼稚ASM表现出诱导的IL-1 β mRNA表达和蛋白释放上调，与ASM收缩和舒张反应性的促哮喘样变化相关，并且这些作用在用IL-1 ra预处理的组织中被消融。综上所述，这些观察结果提供了新的证据，即（a）Th 2细胞因子IL-5和多效性促炎细胞因子IL-1 β由特应性哮喘致敏的ASM内源性释放，并机械地相互作用以介导ASM反应性中的促哮喘扰动;和（B）这种相互作用的性质由IL 5的初始内源性释放给出，其随后通过致敏的ASM自身诱导IL-1 β的自体释放，导致其促哮喘表型的自分泌表现。
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 ofIL-5. This was followed (after 6 hours of incubation) by an enhanced mRNA expression and release of IL-1 beta 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-1 beta 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-1 beta 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 IL5, which then acts to induce the autologous release of IL-1 beta by the sensitized ASM itself, resulting in its autocrine manifestation of the proasthmatic phenotype.