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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Article

Regulation of TH1- and TH2-type cytokine expression and action in atopic asthmatic sensitized airway smooth muscle

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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Comparison of expression of interleukin-4 (IL-4), interleukin-5 (IL-5), ...
Comparison of expression of interleukin-4 (IL-4), interleukin-5 (IL-5), and granulocyte–macrophage colony-stimulating factor (GM-CSF) mRNAs using RT-PCR and Southern blot analysis (a) and Northern blot analysis (b), respectively, in human ASM cells after 0-, 3-, 6-, and 24-h treatment with control serum vs. atopic asthmatic–sensitizing serum. Expression of ribosomal protein L7 (RPL7) (a) and glyceraldehyde phosphate dehydrogenase (GAPDH) (b) mRNAs, respectively, were used to control for gel loading. The blots were probed with human specific IL-4, IL-5, GM-CSF, RPL7, and GAPDH-32P-labeled cDNA probes (see Methods). In contrast to undetectable expression of IL-4, human ASM cells expressed mRNAs for the TH2-type cytokines, IL-5, (a) and GM-CSF (b). Additionally, relative to control serum–treated cells, the mRNA signals of IL-5 and GM-CSF were markedly increased in the atopic asthmatic serum–sensitized cells at 3 and 6 h, whereas expression of the constitutively expressed RPL7 and GAPDH genes was unaltered. Accordingly, corrected for the constitutively expressed mRNAs for RPL7 and GAPDH, relative to their respective controls, the corresponding mRNA signals for IL-5 and GM-CSF were increased at 6 h by approximately eightfold and fivefold, respectively. ASM, airway smooth muscle; RT, reverse transcriptase; TH, T helper.