Autocrine interaction between IL-5 and IL-1 beta mediates altered responsiveness of atopic asthmatic sensitized airway smooth muscle

T-helper type 2 (Th2) cytokines have been implicated in the pathogenesis of the pulmonary inflammatory response and altered bronchial responsiveness i n allergic asthma. To elucidate the mechanism of Th2-dependent mediation of altered airway responsiveness in the atopic asthmatic state, the expressio n and actions of specific cytokines were examined in isolated rabbit and hu man airway smooth muscle (ASM) tissues and cultured cells passively sensiti zed with sera from atopic asthmatic patients or nonatopic/nonasthmatic (con trol) subjects. Relative to control tissues, the atopic asthmatic sensitize d ASM exhibited significantly enhanced maximal isometric contractility to a cetylcholine and attenuated relaxation responses to isoproterenol. These pr oasthmatic changes in agonist responsiveness were ablated by pretreating th e atopic sensitized tissues with either an IL-5 receptor blocking antibody (IL-5ra) or the human recombinant IL-1 receptor antagonist (IL-1ra), wherea s an IL-4 neutralizing antibody had no effect. Moreover, relative to contro ls, atopic asthmatic sensitized ASM cells demonstrated an initial, early (a fter 3 hours of incubation) increased mRNA expression and protein release o fIL-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 i n sensitized cells pretreated with IL-5ra. Extended studies demonstrated th at naive ASM exposed to exogenously administered IL-5 exhibited an induced upregulated mRNA expression and protein release of IL-1 beta associated wit h proasthmatic-like changes in ASM constrictor and relaxant responsiveness, and that these effects were ablated in tissues pretreated with IL-1ra. Tak en together, these observations provide new evidence that (a) the Th2 cytok ine IL-5 and the pleiotropic proinflammatory cytokine IL-1 beta are endogen ously released by atopic asthmatic sensitized ASM and mechanistically inter act 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 th e sensitized ASM itself, resulting in its autocrine manifestation of the pr oasthmatic phenotype.