Source: Annual Congress 2001 - Molecular and cellular pathology of asthma
Disease area: Airway diseases

Abstract

Control of Th1/Th2-cell balance may play a role in the development of asthma. In rodents and humans, nitric oxide (NO) interferes with the JAK3-STAT5 pathway, leading to reversible inhibition of T-cell proliferation. Enhanced sensitivity of Th1 vs. Th2-cells may explain an altered Th1/Th2-balance. The exact mechanisms of NO-mediated T-cell functions are unknown.
We investigated proliferation-rates of murine spleen cells, human Th1-and Th2-clones, and human mononuclear cells to compare them to the dephosphorylation of the respective STATs assessed by electrophoretic-mobility shift assays. We found dephosphorylation of STAT5 after withdrawal of IL-2 and inhibition of proliferation in human T-cell clones as well as in human mononuclear cells under the influence of NO generated by (S)-nitroso-acetyl-penicillamine (SNAP). Restimulation with IL-2 showed a reconstitution of STAT5-phosphorylation in all cells investigated. When NO was present, there was reduced rephosphorylation of STAT5 in the human and the murine system. In the presence of IL-2, dephosphorylation of STAT5 caused by NO was observed after 4-8 hours.
Experiments using inhibitors of the guanylate cyclase showed a reconstitution of the proliferative capacity of T-cells in the presence of NO. We conclude that the inhibition of T-cell proliferation induced by NO is mediated via cyclic GMP. We propose a novel mechanism by which NO activates guanylate cyclase to augment cGMP which induces activation of cGMP-dependent phosphatases ultimately dephosphorylating Tyrosine kinases as well as STATs.

Rating:

Share or cite this content

Citations should be made in the following way:
U. Egermann, R. M. Bingisser (Basel, Switzerland). Regulation of T-cell proliferation by the cyclic nucleotide cGMP. Eur Respir J 2001; 16: Suppl. 31, 3552

Member's Comments

No comment yet.

Related content which might interest you: Modulation by cAMP of IL-1β-induced eotaxin and MCP-1 expression and release in human airway smooth muscle cells Source: Eur Respir J 2003; 22: 220-226 Year: 2003 β-adrenergic receptor-mediated growth of human airway epithelial cell lines Source: Eur Respir J 2002; 20: 353-358 Year: 2002 AMP affects intracellular Ca2+ signalling, migration, cytokine secretion and T-cell priming capacity of human dendritic cells Source: Annual Congress 2009 - Airway cell biology Year: 2009 Differential role of EPAC and PKA in the transduction of cAMP-mediated inhibition of human lung fibroblast proliferation and collagen synthesis Source: Annual Congress 2009 - Pathological remodelling in chronic lung disease: from epithelial-mesenchymal transition to cellular activation Year: 2009 Inhibition of basophil activation by adenosine and its agonists Source: Eur Respir J 2001; 18: Suppl. 33, 532s Year: 2001 Inhibition by reproterol of cAMP phosphodiesterase in cultured P815111 mouse mastocytoma cells Source: Eur Respir J 2001; 18: Suppl. 33, 407s Year: 2001 Cortisol modulates histamine receptors mRNA expression and cyclic nucleotide levels in lymphocytes of asthmatic and healthy subjects Source: Eur Respir J 2004; 24: Suppl. 48, 134s Year: 2004 Effects of histamine and leukotriene antagonism on mannitol and adenosine monophosphate (AMP) challenge Source: Eur Respir J 2002; 20: Suppl. 38, 386s Year: 2002 Modulation of vascular progenitor cell differentiation by TGFß and endothelin-1 receptor inhibition Source: Annual Congress 2009 - Pathobiology of pulmonary vascular diseases Year: 2009 5-Hydroxytryptamine modulates migration, cytokine and chemokine release and T-cell priming capacity of human dendritic cells Source: Annual Congress 2009 - Airway cell biology Year: 2009 Effects of triptolide on T lymphocyte activation and transcription of interleukin-5 gene and its mechanisms Source: Eur Respir J 2003; 22: Suppl. 45, 483s Year: 2003 Oral presentation: Crosstalk of TGF-beta and Ect2, a guanine nucleotide exchange factor for Rho GTPases, controls alveolar epithelial cell proliferation Source: Lung Science Conference 2009 - Cell proliferation, Differentiation and Carcinogenesis Year: 2009 Effect of sildenafil on acrolein-induced airway inflammation and mucus production in rats Source: Eur Respir J 2009; 33: 1122-1132 Year: 2009 beta2-Agonists block tussive responses in guinea pigs via an atypical cAMP-dependent pathway Source: Eur Respir J 2010; 35: 647-654 Year: 2010 Crosstalk of TGF-β and Ect2, a guanine nucleotide exchange factor for Rho GTPases, controls alveolar epithelial cell proliferation Source: Annual Congress 2009 - Pathological remodelling in chronic lung disease: from epithelial-mesenchymal transition to cellular activation Year: 2009 GB001 potently inhibits PGD2 metabolite-induced DP2-mediated cell signaling and eosinophil activation Source: Virtual Congress 2020 – Asthma science: novel targets and mechanisms Year: 2020 Fevipiprant antagonises prostaglandin D2-induced activation of type-2 CD8 T cells (Tc2) Source: International Congress 2019 – Novel targets and mechanisms in asthma Year: 2019 Involvement of human bronchial epithelial cells in proliferation control of T-cells via reversible STAT5 dephosphorylation mediated by nitric oxide (NO) Source: Eur Respir J 2002; 20: Suppl. 38, 207s Year: 2002 Extracellular ATP enhances lung endothelial cell barrier Source: Annual Congress 2005 - Cellular and molecular approaches to lung injury research Year: 2005 A differential role for ceramide kinase in antigen/FcεRI mediated mast cell activation and function Source: Eur Respir J 2006; 28: Suppl. 50, 231s Year: 2006