IL-1β-Induced Accumulation of Amyloid: Macroautophagy in Skeletal Muscle Depends on ERK.
The pathology of inclusion body myositis (IBM) involves an inflammatory response andβ-amyloid deposits in muscle fibres. It is believed that MAP kinases such as the ERK signalling pathway mediate the inflammatory signalling in cells. Further, there is evidence that autophagic activity plays a crucial role in the pathogenesis of IBM. Using a well established in vitro model of IBM, the autophagic pathway, MAP kinases, and accumulation ofβ-amyloid were examined. We demonstrate that stimulation of muscle cells with IL-1βand IFN-γled to an increased phosphorylation of ERK. The ERK inhibitor PD98059 diminished the expression of proinflammatory markers as well as the accumulation ofβ-amyloid. In addition, IL-1βand IFN-γled to an increase of autophagic activity, upregulation of APP, and subsequent accumulation ofβ-sheet aggregates. Taken together, the data demonstrate that the ERK pathway contributes to formation ofβ-amyloid and regulation of autophagic activity in muscle cells exposed to proinflammatory cell stress. This suggests that ERK serves as an important mediator between inflammatory mechanisms and protein deposition in skeletal muscle and is a crucial element of the pathology of IBM.
Department of Neurology, University Medical Center Göttingen, Göttingen, Germany.
Karsten
K
Schmidt
Department of Neurology, University Medical Center Göttingen, Göttingen, Germany.
Magdalena
M
Wienken
Department of Neurology, University Medical Center Göttingen, Göttingen, Germany; Institute of Experimental Immunology, Laboratory of Neuroinflammation, University of Zürich, Zürich, Switzerland.
Christian W
CW
Keller
Department of Trauma Surgery, Orthopaedics and Plastic Surgery, University Medical Center Göttingen, Göttingen, Germany; Arcus Klinik, Pforzheim, Germany.
Peter
0000-0001-7172-133X
P
Balcarek
Institute of Experimental Immunology, Laboratory of Viral Immunobiology, University of Zürich, Zürich, Switzerland.
Christian
C
Münz
Department of Neurology, University Medical Center Göttingen, Göttingen, Germany.
Jens
0000-0002-5589-2371
J
Schmidt
D000682:Amyloid / Q000378:metabolism*; D000071182:Autophagosomes / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D015153:Blotting, Western; D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D032446:Myoblasts / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects
D000682:Amyloid; D053583:Interleukin-1beta; D007371:Interferon-gamma; D048049:Extracellular Signal-Regulated MAP Kinases