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 fiber atrophy in dermatomyositis (DM). These proteins included proteases (cathepsins B and L, calpain), proteins implicated in apoptosis and cell cycle (Bcl-x(l), Fas, p21), structural proteins (beta-actin, utrophin, desmin), and other proteins whose expression is known to be modified by IFN-gamma (neural cell adhesion molecule (N-CAM), major histocompatibility complex-I (MHC-I)). We performed immunocytochemistry, Western blot, and semiquantitative reverse transcriptase-polymerase chain reaction using human muscle cultures. We found upregulation of cathepsins B and L, bcl-x(l) and p21 while N-CAM, calpain, utrophin, desmin, beta-actin and Fas remained at basal levels. Immunohistochemistry on frozen sections from biopsies of patients with different muscle diseases showed upregulation of cathepsin L and calpain in perifascicular muscle fibers in DM. In view of these results, the increased expression of cathepsins L and B after IFN-gamma stimulation in muscle cultures and its inhibition using fludarabine, a STAT1 blocker, further support our previous studies and suggest that the increased expression of cathepsins detected in perifascicular muscle fibers in DM is mediated by IFN-gamma/STAT1 and contributes to their atrophy.
Gallardo
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Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma Barcelona, Spain.
de Andrés
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I
Illa
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D000328:Adult; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000502:physiology; D001706:Biopsy; D002401:Cathepsin B / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D056668:Cathepsin L; D002403:Cathepsins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D003882:Dermatomyositis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000235:genetics / Q000494:pharmacology*; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000737:chemistry / Q000166:cytology / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D012038:Regeneration / Q000502:physiology; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015534:Trans-Activators / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology
D000970:Antineoplastic Agents; D017931:DNA Primers; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D007371:Interferon-gamma; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; C534281:CTSL protein, human; D056668:Cathepsin L; D014740:Vidarabine; C024352:fludarabine