title: CRAC channel inhibition produces greater anti-inflammatory effects than glucocorticoids in CD8 cells from COPD patients.
abstract: 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.
authors.affiliation: *University of Manchester NIHR Translational Research Facility, Manchester Academic Health Science Centre, University Hospital of South Manchester Foundation Trust, Manchester M23 9LT, U.K.
authors.forename: Seamus
authors.initials: S
authors.lastname: Grundy
authors.forename: Manminder
authors.initials: M
authors.lastname: Kaur
authors.forename: Jonathan
authors.initials: J
authors.lastname: Plumb
authors.forename: Sophie
authors.initials: S
authors.lastname: Reynolds
authors.forename: Simon
authors.initials: S
authors.lastname: Hall
authors.forename: David
authors.initials: D
authors.lastname: House
authors.forename: Malcolm
authors.initials: M
authors.lastname: Begg
authors.forename: David
authors.initials: D
authors.lastname: Ray
authors.forename: Dave
authors.initials: D
authors.lastname: Singh
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000473:pathology*; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D016022:Case-Control Studies; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology / Q000627:therapeutic use; D016207:Cytokines / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D000893:Anti-Inflammatory Agents; D002121:Calcium Channel Blockers; D016207:Cytokines; D005938:Glucocorticoids; D050778:NFATC Transcription Factors; D003907:Dexamethasone; D016572:Cyclosporine
references.citation: Pharmacogenomics. 2010 Oct;11(10):1491-501
references.pmid: 21047207
references.citation: Endocr Rev. 2003 Aug;24(4):488-522
references.pmid: 12920152
references.citation: Cochrane Database Syst Rev. 2012 Jul 11;(7):CD002991
references.pmid: 22786484
references.citation: J Immunol. 2010 Nov 15;185(10):5845-58
references.pmid: 20956344
references.citation: Am J Pathol. 2007 Sep;171(3):767-76
references.pmid: 17640964
references.citation: Annu Rev Immunol. 1997;15:707-47
references.pmid: 9143705
references.citation: Am J Med. 2002 Jul;113(1):59-65
references.pmid: 12106623
references.citation: N Engl J Med. 2004 Jun 24;350(26):2645-53
references.pmid: 15215480
references.citation: Proc Am Thorac Soc. 2006 Aug;3(6):487-8
references.pmid: 16921122
references.citation: Mol Immunol. 2013 Jul;54(3-4):355-67
references.pmid: 23357789
references.citation: Am J Respir Crit Care Med. 2008 Nov 15;178(10):1002-8
references.pmid: 18787222
references.citation: Eur Respir J. 2009 Jul;34(1):219-30
references.pmid: 19567605
references.citation: Am J Respir Crit Care Med. 1997 Mar;155(3):852-7
references.pmid: 9117016
references.citation: Pulm Pharmacol Ther. 2011 Aug;24(4):367-72
references.pmid: 21463700
references.citation: Nat Rev Immunol. 2005 Jun;5(6):472-84
references.pmid: 15928679
references.citation: Respir Res. 2012 Mar 14;13:20
references.pmid: 22417244
references.citation: Eur Respir J. 2001 Jul;18(1):45-52
references.pmid: 11510804
references.citation: J Allergy Clin Immunol. 2012 Jun;129(6):1628-35.e2
references.pmid: 22409987
references.citation: Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):752-6
references.pmid: 8290595
references.citation: Cell Calcium. 2011 Sep;50(3):261-9
references.pmid: 21665274
references.citation: ChemMedChem. 2009 May;4(5):706-18
references.pmid: 19330784
references.citation: J Immunol. 2009 Mar 1;182(5):3270-7
references.pmid: 19234225
references.citation: Cell Calcium. 2007 Aug;42(2):145-56
references.pmid: 17572487
references.citation: Am J Respir Crit Care Med. 1998 Mar;157(3 Pt 1):822-6
references.pmid: 9517597
references.citation: Nat Med. 2007 May;13(5):567-9
references.pmid: 17450149
references.citation: Am J Respir Crit Care Med. 1996 Feb;153(2):509-14
references.pmid: 8564089
references.citation: Am J Respir Crit Care Med. 2001 Aug 1;164(3):469-73
references.pmid: 11500352
references.citation: Ann N Y Acad Sci. 2005 Jun;1051:658-65
references.pmid: 16127006
references.citation: Drugs. 2007;67(11):1531-9
references.pmid: 17661526
references.citation: N Engl J Med. 2009 Jun 4;360(23):2445-54
references.pmid: 19494220
references.citation: J Immunol. 2009 Sep 1;183(5):3454-62
references.pmid: 19648266
references.citation: J Immunol. 2010 Jun 1;184(11):6504-13
references.pmid: 20427767
references.citation: Ann Allergy Asthma Immunol. 1995 Jul;75(1):65-72
references.pmid: 7621064