RT Journal Article
SR Electronic
T1 Impact of cigarette smoke on function and expression of immunoproteasomes
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 3247
VO 44
IS Suppl 58
A1 Ilona Keller
A1 Angela Dann
A1 Oliver Vosyka
A1 Shinji Takenaka
A1 Petra Nathan
A1 Oliver Eickelberg
A1 Silke Meiners
YR 2014
UL http://erj.ersjournals.com/content/44/Suppl_58/3247.abstract
AB Cigarette smoke (CS) is the main cause of chronic obstructive pulmonary disease (COPD). While there is profound evidence for involvement of MHC II-mediated immune responses in COPD pathogenesis, MHC I-mediated immunity, however, has not been investigated in detail. MHC I antigen presentation requires the breakdown of cellular proteins by the proteasome.Here, we analyzed the effects of CS on the composition and activity of the proteasome. In particular, we focused on a specialized form of proteasome, namely the immunoproteasome (IP), whose proteolytic activities contribute to improved generation of antigenic peptides.The catalytic IP subunits LMP2 and LMP7 are present at low levels in parenchymal cells of the lung such as alveolar and bronchial epithelial cells and fibroblasts, but can be rapidly induced by treatment with IFNγ. Repeated treatment of epithelial A549 or fibroblast HFL-1 cells with CS extract not only reduced basal IP expression but also attenuated IFNγ mediated induction of IP. In contrast, immune cells, such as splenocytes and spleen-derived dendritic cells, responded to CS treatment by further increasing IP expression. Importantly, MHC I-mediated antigen presentation was severely impaired in CS-treated cells as evidenced by two independent antigen presentation assays. In vivo, immune cells of the lung revealed altered IP expression in response to smoke. Low parenchymal but high immune cell-mediated expression of the IP-subunit LMP2 was also observed in COPD tissues as determined by immunohistochemical analysis.Our data suggest that altered MHC I antigen presentation in response to CS might contribute to the pathogenesis of COPD.