Human bronchial epithelium controls TH2 responses by TH1-induced, nitric oxide-mediated STAT5 dephosphorylation: implications for the pathogenesis of asthma

Eriksson, Urs; Egermann, Ulrich; Bihl, Michel P; Gambazzi, Franco; Tamm, Michael; Holt, Patrick G; Bingisser, Roland M (2005). Human bronchial epithelium controls TH2 responses by TH1-induced, nitric oxide-mediated STAT5 dephosphorylation: implications for the pathogenesis of asthma. Journal of immunology, 175(4), pp. 2715-20. Bethesda, Md.: American Association of Immunologists

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Increased levels of NO in exhaled air in association with increased NO synthetase (NOS)2 expression in bronchial epithelial are hallmark features of asthma. It has been suggested that NO contributes to asthma pathogenesis by selective down-regulation of TH1 responses. We demonstrate, however, that NO can reversibly limit in vitro expansion of both human TH1 and TH2 CD4+ T cells. Mechanistically, NO induces cGMP-mediated reversible STAT5 dephosphorylation and therefore interferes with the IL-2R activation cascade. Human bronchial epithelial cells (HBEC) up-regulate NOS2 after stimulation with IFN-gamma secreted by TH1 CD4+ T cells and release NO, which inhibits both TH1 and TH2 cell proliferation. This reversible T cell growth arrest depends on NO because T cell proliferation is completely restored after in vitro blocking of NOS2 on HBEC. HBEC thus drive the effector end of a TH1-controlled feedback loop, which protects airway mucosal tissues at the potential lesional site in asthma from overwhelming CD4+ TH2 (and potentially TH1) responses following allergen exposure. Variations in the efficiency of this feedback loop provides a plausible mechanism to explain why only a subset of atopics sensitized to ubiquitous aeroallergens progress to expression of clinically relevant levels of airways inflammation.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Endocrinology, Diabetology and Clinical Nutrition
UniBE Contributor:	Egermann, Ulrich
ISSN:	0022-1767
Publisher:	American Association of Immunologists
Language:	English
Submitter:	Factscience Import
Date Deposited:	04 Oct 2013 15:23
Last Modified:	05 Dec 2022 14:25
PubMed ID:	16081849
Web of Science ID:	000232010400086
URI:	https://boris.unibe.ch/id/eprint/37246 (FactScience: 207261)