Human bronchial epithelium controls TH2 responses by TH1-induced, nitric oxide-mediated STAT5 dephosphorylation: implications for the pathogenesis of asthma.
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.
Eriksson
Urs
U
Experimental Critical Care Medicine, Department of Research, Basel University Hospital, Switzerland.
Egermann
Ulrich
U
Bihl
Michel P
MP
Gambazzi
Franco
F
Tamm
Michael
M
Holt
Patrick G
PG
Bingisser
Roland M
RM
D001249:Asthma / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D001980:Bronchi; D049109:Cell Proliferation; D002478:Cells, Cultured; D002999:Clone Cells; D018920:Coculture Techniques; D006152:Cyclic GMP / Q000502:physiology; D004790:Enzyme Induction / Q000276:immunology; D006131:Growth Inhibitors / Q000502:physiology; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology; D008213:Lymphocyte Activation / Q000276:immunology; D009569:Nitric Oxide / Q000378:metabolism / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D010766:Phosphorylation; D020545:Respiratory Mucosa / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
D006131:Growth Inhibitors; D050799:STAT5 Transcription Factor; D009569:Nitric Oxide; D007371:Interferon-gamma; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D006152:Cyclic GMP