Cathepsins are upregulated by IFN-gamma/STAT1 in human muscle culture: A possible active factor in dermatomyositis

The aim of this work was to study which genes upregulated by the IFN-gamma /STAT1 system in human muscle might be involved in the process of muscle fi ber atrophy in dermatomyositis (DM). These proteins included proteases (cat hepsins B and L, calpain), proteins implicated in apoptosis and cell cycle (Bcl-x(1), Fas, p21), structural proteins (beta -actin, utrophin, desmin), and other proteins whose expression is known to be modified by IFN-gamma (n eural cell adhesion molecule (N-CAM), major histocompatibility complex-I (M HC-I)). We performed immunocytochemistry, Western blot, and semiquantitativ e reverse transcriptase-polymerase chain reaction using human muscle cultur es. We found upregulation of cathepsins B and L, bcl-x(1) and p21 while N-C AM, calpain, utrophin, desmin, beta -actin and Fas remained at basal levels . Immunohistochemistry on frozen sections from biopsies of patients with di fferent muscle diseases showed upregulation of cathepsin L and calpain in p erifascicular muscle fibers in DM. In view of these results, the increased expression of cathepsins L and B after IFN-gamma stimulation in muscle cult ures and its inhibition using fludarabine, a STAT1 blocker, further support our previous studies and suggest that the increased expression of cathepsi ns detected in perifascicular muscle fibers in DM is mediated by IFN-gamma /STAT1. and contributes to their atrophy.