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Regulation of TH1- and TH2-type cytokine expression and action in atopic asthmatic sensitized airway smooth muscle
Hakon Hakonarson, … , Carrie Carter, Michael M. Grunstein
Hakon Hakonarson, … , Carrie Carter, Michael M. Grunstein
Published April 1, 1999
Citation Information: J Clin Invest. 1999;103(7):1077-1087. https://doi.org/10.1172/JCI5809.
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Regulation of TH1- and TH2-type cytokine expression and action in atopic asthmatic sensitized airway smooth muscle

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Abstract

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.

Authors

Hakon Hakonarson, Neil Maskeri, Carrie Carter, Michael M. Grunstein

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Figure 4

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Comparison of mRNA expression of the TH1-type cytokine receptors for IL-...
Comparison of mRNA expression of the TH1-type cytokine receptors for IL-2, IL-12, and IFN-γ (a), and of the TH2-type cytokine receptors for IL-5 and GM-CSF (b) using RT-PCR after exposure of human ASM cells for 0, 3, 6, and 24 h to human control serum vs. human atopic asthmatic sensitizing serum. Expression of RPL7 was used to control for gel loading. The blots were probed with human specific IL-2, IL-12, IFN-γ, IL-5, and GM-CSF 32P-labeled cDNA probes (see Methods). In contrast to undetectable expression of the IL-12 receptor (IL-12r) mRNA, cells expressed mRNAs of the TH1 receptors for IL-2 and IFN-γ (a), and of the TH2 receptors for IL-5 and GM-CSF (b). Moreover, relative to control serum–treated cells, expression of IL-5 and GM-CSF receptor (GM-CSFr) mRNAs was notably increased at 3 h and thereafter in the atopic asthmatic serum–sensitized cells, whereas expression of IL-2 and IFN-γ receptor mRNAs was increased subsequently at 6 h and thereafter. Constitutively expressed RPL7 mRNA was similar under control and atopic asthmatic serum–treated conditions. Accordingly, corrected to RPL7 expression, relative to their respective controls, the IL-2 and IFN-g receptor mRNA signals were increased at 6 h by 4.5-fold and ∼4-fold, respectively.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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