The inhibition of apoptosis in myositis and in normal muscle cells

The mechanism of injury and death of muscle cells in the inflammatory myopa thies (dermatomyositis, polymyositis, and inclusion body myositis) remains obscure, We and others have not detected apoptosis in the muscle biopsies f rom patients with myositis despite clear evidence of cell damage and loss. We provide evidence in this study that Fas ligand (FasL) as well as Fas is present on muscle cells and inflammatory cells in myositis biopsies: Fas is present on most muscle cells and lymphocytes, and Fast is present on degen erating muscle cells and many infiltrating mononuclear cells, The expressio n of both Pas and Fast in the inflamed tissue makes the absence of apoptosi s more striking. To address the mechanisms of this resistance to classical apoptosis in muscle cells, we have investigated the expression of the antia poptotic molecule FLICE (Fas-associated death domain-like IL-1-converting e nzyme)-inhibitory protein (FLIP) in muscle biopsies of myositis patients an d in cultured human skeletal muscle cells. Using laser capture microscopy, we have shown that FLIP is expressed in the muscle fibers and on infiltrati ng lymphocytes of myositis biopsies. Furthermore, we have shown that FLIP, but not Bcl-2, is expressed in cultured human skeletal muscle cells stimula ted with proinflammatory cytokines, and inhibition of FLIP with antisense o ligonucleotides promotes significant cleavage of poly(ADP-ribose) polymeras e autoantigen, a sensitive indicator of apoptosis. These studies strongly s uggest that the resistance of muscle to Fas-mediated apoptosis is due to th e expression of FLIP in muscle cells in the inflammatory environment in myo sitis.