| Abstract | Oxidative stress and nuclear factor-kappaB (NF-kappaB) activation are linked to the pathogenesis of many metabolic, degenerative, and chronic inflammatory diseases. Activation of the receptor for advanced glycation end products (RAGE) by its specific ligand N(epsilon)-carboxymethyllysine (CML) results in the activation of NF-kappaB and the production of proinflammatory cytokines. To determine whether engagement of RAGE contributes to the pathogenesis of inflammatory myopathies, we performed immunohistochemical studies on the presence of CML-modified proteins, RAGE and activated NF-kappaB in muscle biopsies of patients with polymyositis (PM, n=10), dermatomyositis (DM, n=10), limb girdle muscular dystrophy (LGMD, n=10) and in 10 controls with normal muscle biopsy results. In inflammatory myopathies CML, RAGE and NF-kappaB were detected in mononuclear cells and in regenerating muscle fibers. CML, NF-kappaB and, to a lesser extent, RAGE were also found in degenerating muscle fibers, but colocalization of CML, RAGE and NF-kappaB was only seen in infiltrating mononuclear cells and regenerating muscle fibers. Immunofluorescence double labeling demonstrated an expression of CML, RAGE and NF-kappaB in CD4-, CD8-, CD22- and CD68-positive mononuclear cells. Western blot analysis showed an increased immunoreactivity for CML-modified proteins in PM and DM. In LGMD, CML, RAGE and NF-kappaB were found in regenerating muscle fibers and less frequently in degenerating muscle fibers, and with lower staining intensities than in inflammatory myopathies. Our data suggests that the CML-RAGE-NF-kappaB pathway is an evident proinflammatory pathomechanism in mononuclear effector cells in PM and DM. RAGE-mediated NF-kappaB activation may be involved in muscle fiber regeneration in inflammatory myopathies and LGMD. |
| Authors | K M Haslbeck, U Friess, E D Schleicher, A Bierhaus, P P Nawroth, A Kirchner, E Pauli, B Neundörfer, D Heuss
(Affiliation: Department of Neurology, University Erlangen-Nürnberg, Schwabachanlage 6, 91054, Erlangen, Germany, matthias.haslbeck at neuro.imed.uni-erlangen.de)
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| Journal | Acta neuropathologica
(Acta Neuropathol)
Vol. 110
Issue 3
Pg. 247-54
(Sep 2005)
ISSN: 0001-6322 Germany |
| PMID | 15986224
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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| Chemical References |
- Glycosylation End Products, Advanced
- NF-kappa B
- Receptors, Immunologic
- advanced glycosylation end-product receptor
- Lysine
- N(6)-carboxymethyllysine
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| Topics |
- Adult
- Aged
- Dermatomyositis
(immunology, metabolism, physiopathology)
- Glycosylation End Products, Advanced
- Humans
- Immunohistochemistry
- Leukocytes, Mononuclear
(immunology, metabolism)
- Lysine
(analogs & derivatives, metabolism)
- Middle Aged
- Muscle Fibers, Skeletal
(metabolism, pathology)
- Muscle, Skeletal
(immunology, metabolism, physiopathology)
- Muscular Dystrophies, Limb-Girdle
(immunology, metabolism, physiopathology)
- Myositis
(immunology, metabolism, physiopathology)
- NF-kappa B
(metabolism)
- Polymyositis
(immunology, metabolism, physiopathology)
- Receptors, Immunologic
(immunology, metabolism)
- Regeneration
(physiology)
- Signal Transduction
- Transcriptional Activation
(physiology)
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