There are increased numbers of pulmonary CD8 lymphocytes in COPD (chronic obstructive pulmonary disease). CRAC (calcium release-activation calcium) channels play a central role in lymphocyte activation though the regulation of the transcription factor NFAT (nuclear factor of activated T-cells). We studied the expression of NFAT in lungs from COPD patients compared with controls, and evaluated the effects of CRAC channel inhibition compared with corticosteroids on NFAT activation and cytokine production in CD8 cells from COPD patients. The effects of the corticosteroid dexamethasone, the calcineurin inhibitor cyclosporin and the CRAC channel inhibitor Synta 66 were studied on cytokine production and NFAT activation using peripheral blood and isolated pulmonary CD8 cells. NFAT1 and CD8 co-expression in the lungs was compared in COPD patients and controls using combined immunohistochemistry and immunofluorescence. NFAT inhibition with either cyclosporin or Synta 66 resulted in significantly greater maximal inhibition of cytokines than dexamethasone in both peripheral blood and pulmonary CD8 cells [e.g. >95% inhibition of IFNγ (interferon γ) production from pulmonary CD8 cells using cyclosporin and Synta 66 compared with <50% using dexamethasone]. The absolute number of pulmonary CD8 cells co-expressing NFAT1 was significantly raised in lungs from COPD patients compared with controls, but the percentage of CD8 cells co-expressing NFAT1 was similar between COPD patients and controls (80.7% compared with 78.5% respectively, P=0.3). Inhibition of NFAT using the CRAC channel Synta 66 produces greater anti-inflammatory effects on CD8 cells from COPD patients than corticosteroids. NFAT is expressed at a high level in pulmonary CD8 cells in COPD.
CRAC channel inhibition produces greater anti-inflammatory effects than glucocorticoids in CD8 cells from COPD patients
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Seamus Grundy, Manminder Kaur, Jonathan Plumb, Sophie Reynolds, Simon Hall, David House, Malcolm Begg, David Ray, Dave Singh; CRAC channel inhibition produces greater anti-inflammatory effects than glucocorticoids in CD8 cells from COPD patients. Clin Sci (Lond) 1 February 2014; 126 (3): 223–232. doi: https://doi.org/10.1042/CS20130152
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