title: Steroid resistance in COPD is associated with impaired molecular chaperone Hsp90 expression by pro-inflammatory lymphocytes.
abstract: Corticosteroid resistance is a major barrier to effective treatment of COPD. We have shown that the resistance is associated with decreased expression of glucocorticoid receptor (GCR) by senescent CD28nullCD8+ pro-inflammatory lymphocytes in peripheral blood of COPD patients. GCR must be bound to molecular chaperones heat shock proteins (Hsp) 70 and Hsp90 to acquire a high-affinity steroid binding conformation, and traffic to the nucleus. We hypothesized a loss of Hsp70/90 from these lymphocytes may further contribute to steroid resistance in COPD.
  
  
  
  Blood was collected from COPD (n = 10) and aged-matched controls (n = 10). To assess response to steroids, cytotoxic mediators, intracellular pro-inflammatory cytokines, CD28, GCR, Hsp70 and Hsp90 were determined in T and NKT-like cells in the presence of ± 10 μM prednisolone and 2.5 ng/mL cyclosporine A (binds to GCR-Hsp70/90 complex) using flow cytometry, western blot and fluorescence microscopy.
  
  
  
  A loss of expression of Hsp90 and GCR from CD28null CD8+ T and NKT-like cells in COPD was noted (Hsp70 unchanged). Loss of Hsp90 expression correlated with the percentage of CD28null CD8+ T and NKT-like cells producing IFNγ or TNFα in all subjects (eg, COPD: R = -0.763, p = 0.007 for T-cell IFNγ). Up-regulation of Hsp90 and associated decrease in pro-inflammatory cytokine production was found in CD28nullCD8+ T and NKT-like cells in the presence of 10 μM prednisolone and 2.5 ng/mL cyclosporine A.
  
  
  
  Loss of Hsp90 from cytotoxic/pro-inflammatory CD28nullCD8+ T and NKT-like cells could contribute to steroid resistance in COPD. Combination prednisolone and low-dose cyclosporine A therapy inhibits these pro-inflammatory cells and may reduce systemic inflammation in COPD.
authors: Lung Research, Hanson Institute and Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, South Australia, Australia. greg.hodge@sa.gov.au.|Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia. greg.hodge@sa.gov.au.
authors: Greg
authors: G
authors: Hodge
authors: Lung Research, Hanson Institute and Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, South Australia, Australia.|Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors: Eugene
authors: E
authors: Roscioli
authors: Lung Research, Hanson Institute and Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, South Australia, Australia.|Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors: Hubertus
authors: H
authors: Jersmann
authors: Lung Research, Hanson Institute and Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
authors: Hai B
authors: HB
authors: Tran
authors: Lung Research, Hanson Institute and Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, South Australia, Australia.|Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors: Mark
authors: M
authors: Holmes
authors: Lung Research, Hanson Institute and Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, South Australia, Australia.|Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors: Paul N
authors: PN
authors: Reynolds
authors: Lung Research, Hanson Institute and Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, South Australia, Australia.|Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors: Sandra
authors: S
authors: Hodge
mesh_terms: D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D018106:CD28 Antigens / Q000097:blood; D016022:Case-Control Studies; D016572:Cyclosporine / Q000494:pharmacology; D016207:Cytokines / Q000097:blood; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D018840:HSP70 Heat-Shock Proteins / Q000097:blood; D018841:HSP90 Heat-Shock Proteins / Q000097:blood*; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008875:Middle Aged; D010641:Phenotype; D011239:Prednisolone / Q000494:pharmacology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000097:blood; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
chemical_list: D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D018106:CD28 Antigens; D016207:Cytokines; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D011965:Receptors, Glucocorticoid; D016572:Cyclosporine; D011239:Prednisolone
keywords: CD28nullCD8+ T and NKT-like cells; COPD; Hsp90; IFNγ and TNFα; Lymphocyte senescence