Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Antineoplastic Agents / metabolism
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Antineoplastic Agents / pharmacology*
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Apoptosis / physiology
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Biopsy
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Cathepsin B / analysis
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Cathepsin B / genetics*
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Cathepsin B / metabolism
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Cathepsin L
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Cathepsins / analysis
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Cathepsins / genetics*
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Cathepsins / metabolism
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Cell Cycle / physiology
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Cells, Cultured
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Cysteine Endopeptidases
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DNA Primers
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DNA-Binding Proteins / analysis
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism
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Dermatomyositis / metabolism*
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Dermatomyositis / pathology
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Dermatomyositis / physiopathology
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Gene Expression / drug effects
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Gene Expression / physiology
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Humans
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Immunohistochemistry
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Interferon-gamma / genetics
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Interferon-gamma / pharmacology*
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Middle Aged
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Muscle Fibers, Skeletal / chemistry
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Muscle Fibers, Skeletal / cytology
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Muscle Fibers, Skeletal / physiology
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Muscle, Skeletal / metabolism
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Muscle, Skeletal / pathology
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RNA, Messenger / analysis
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Regeneration / physiology
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STAT1 Transcription Factor
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Trans-Activators / analysis
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Trans-Activators / genetics*
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Trans-Activators / metabolism
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Vidarabine / analogs & derivatives
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Vidarabine / pharmacology
Substances
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Antineoplastic Agents
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DNA Primers
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DNA-Binding Proteins
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RNA, Messenger
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STAT1 Transcription Factor
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STAT1 protein, human
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Trans-Activators
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Interferon-gamma
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Cathepsins
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Cysteine Endopeptidases
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Cathepsin B
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CTSL protein, human
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Cathepsin L
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Vidarabine
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fludarabine