Brain, Vol. 123, No. 2, 374-379,
February 2000
© 2000 Oxford University Press
Synergistic effect of ß-amyloid protein and interferon gamma on nitric oxide production by C2C12 muscle cells
Institute of Neurology, University of Milan, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
Correspondence to:
Pierluigi Baron, MD, Institute of Neurology, University of Milan, IRCCS Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122 Milan, Italy
Nitric oxide (NO) is an important mediator of diverse physiological and pathological responses. NO-induced oxidative stress has been proposed in the pathogenesis of muscle tissue damage in inclusion-body myositis (IBM), which is characterized by deposition of ß-amyloid protein (Aß) in vacuolated muscle fibres. To determine whether Aß can induce NO production in skeletal muscle, we stimulated C2C12 mouse skeletal muscle cells in vitro with Aß[1–42] or Aß[25–35] peptides in the presence or absence of interferon gamma (IFN-
). Neither Aß peptides nor IFN- were able to stimulate nitrite (NO2–) production by C2C12 cells when given alone. However, combination of IFN- with either Aß[1–42] or Aß[25–35] resulted in significant NO2– release into cell-free supernatants. Northern blot analysis of RNA obtained from Aß/IFN--stimulated C2C12 cells revealed increased mRNA accumulation of inducible nitric oxide synthase (iNOS). Moreover, ~4% of muscle cells incubated with Aß peptides and IFN- showed ultrastructural features of DNA fragmentation. These findings, taken together, indicate that the association of Aß with IFN- stimulates NO2– production via induction of iNOS gene expression in skeletal muscle cells, with occasional evidence for nuclear changes suggesting apoptotic morphology. These data further support a role for Aß deposition in the pathogenesis of postulated oxidative damage in IBM.
nitric oxide; ß-amyloid; muscle cell; IBM; apoptosis
Aß = ß-amyloid protein; ßAPP = ß-amyloid precursor protein; s-IBM = inclusion-body myositis; h-IBM = inclusion-body myopathy; IFN- = interferon gamma; NO = nitric oxide; NOS = nitric oxide synthase; L-NMMA = N
-methyl-L-arginine; DAPI = 4',6'-diamidino-2-phenylindole-dihydrochloride
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