Cathepsins Are Upregulated by IFN-gamma/STAT1 in Human Muscle Culture: A Possible Active Factor in Dermatomyositis

J Neuropathol Exp Neurol. 2001 Sep;60(9):847-55. doi: 10.1093/jnen/60.9.847.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / physiology
  • Biopsy
  • Cathepsin B / analysis
  • Cathepsin B / genetics*
  • Cathepsin B / metabolism
  • Cathepsin L
  • Cathepsins / analysis
  • Cathepsins / genetics*
  • Cathepsins / metabolism
  • Cell Cycle / physiology
  • Cells, Cultured
  • Cysteine Endopeptidases
  • DNA Primers
  • DNA-Binding Proteins / analysis
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Dermatomyositis / metabolism*
  • Dermatomyositis / pathology
  • Dermatomyositis / physiopathology
  • Gene Expression / drug effects
  • Gene Expression / physiology
  • Humans
  • Immunohistochemistry
  • Interferon-gamma / genetics
  • Interferon-gamma / pharmacology*
  • Middle Aged
  • Muscle Fibers, Skeletal / chemistry
  • Muscle Fibers, Skeletal / cytology
  • Muscle Fibers, Skeletal / physiology
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • RNA, Messenger / analysis
  • Regeneration / physiology
  • STAT1 Transcription Factor
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Trans-Activators / analysis
  • Trans-Activators / genetics*
  • Trans-Activators / metabolism
  • Vidarabine / analogs & derivatives
  • Vidarabine / pharmacology

Substances

  • Antineoplastic Agents
  • DNA Primers
  • DNA-Binding Proteins
  • RNA, Messenger
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Trans-Activators
  • Interferon-gamma
  • Cathepsins
  • Cysteine Endopeptidases
  • Cathepsin B
  • CTSL protein, human
  • Cathepsin L
  • Vidarabine
  • fludarabine