CD4 + T helper (TH)1-and TH2-type cytokines reportedly play an important role in the pathobiology of asthma. Recent evidence suggests that proasthmatic changes in airway smooth muscle (ASM) responsiveness may be induced by the autocrine release of certain proinflammatory cytokines by the ASM itself. We examined whether TH1-and TH2-type cytokines are expressed by atopic asthmatic sensitized ASM and serve to autologously regulate the proasthmatic phenotype in the sensitized ASM. Expression of these cytokines and their receptors was examined in isolated rabbit and human ASM tissues and cultured cells passively sensitized with sera from atopic asthmatic patients or control subjects. Relative to controls, atopic sensitized ASM cells exhibited an early increased mRNA expression of the TH2-type cytokines, interleukin-5 (IL-5) and granulocyte-macrophage colony-stimulating factor (GM-CSF), and their receptors. This was later followed by enhanced mRNA expression of the TH1-type cytokines, IL-2, IL-12, and interferon-γ (IFN-γ), as well as their respective receptors. In experiments on isolated ASM tissue segments (a) exogenous administration of IL-2 and IFN-γ to atopic asthmatic serum-sensitized ASM ablated both their enhanced constrictor responsiveness to acetylcholine (ACh) and their attenuated relaxation responsiveness to β-adrenoceptor stimulation with isoproterenol, and (b) administration of IL-5 and GM-CSF to naive ASM induced significant increases in their contractility to ACh and impaired their relaxant responsiveness to isoproterenol. Collectively, these observations provide new evidence demonstrating that human ASM endogenously expresses both TH1-and TH2-type cytokines and their receptors, that these molecules are sequentially upregulated in the atopic asthmatic sensitized state, and that they act to downregulate and upregulate proasthmatic perturbations in ASM responsiveness, respectively.J. Clin. Invest. 103:1077-1087 (1999. fluid levels of IL-4 and IL-5, as well as the percentage of cells expressing these cytokines, whereas IFN-γ levels and cells expressing IFN-γ in the lung are increased (22)(23)(24).Although this evidence implies an important role for CD4 + TH cells in the pathobiology of atopic asthma, we have recently demonstrated (25)(26)(27))that the ASM itself can be induced to express specific cytokines, notably IL-1β, in the atopic asthmatic sensitized state and, thereby, the ASM acts in an autocrine manner to manifest endogenously its proasthmatic phenotypic responsiveness. In view of the latter, together with the aforementioned implied role of an altered TH1/TH2 cytokine profile in allergic asthma, the present study examined whether isolated rabbit and human ASM (HASM) tissue and cultured ASM cells also express TH1-and TH2-type cytokines and their receptors, whether the expression of these molecules is perturbed in the atopic asthmatic sensitized state, and whether the latter perturbation is associated with proasthmatic changes in agonist-mediated ASM constrictor and relaxant responsiveness. The resu...
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