CYTOKINES, SIGNAL-TRANSDUCTION, AND INFLAMMATORY DEMYELINATION - REVIEW AND HYPOTHESIS

The mechanism of focal demyelination in multiple sclerosis has been a long-standing enigma of this disorder. Cytokines, a diverse family of signalling molecules, are viewed as potential mediators of the process based on clinical observations and studies with animal models and tis sue/cell culture systems. Myelin and oligodendrocyte (OL) destruction occur in cultured preparations subjected to cytokines such as tumor ne crosis factor-alpha (TNF alpha) and lymphotoxin (LT). Many studies hav e shown these and other cytokines to be elevated at lesion sites and i n the CSF of multiple sclerosis (MS) patients, with similar findings i n animal models. Some variability in the nature of MS lesion formation has been reported, both OLs and myelin being primary targets. To acco unt for myelin destruction in the presence of apparently functional OL s we hypothesize that cytokines such as TNF alpha and LT alpha contrib ute to myelin damage through triggering of specific reactions within t he myelin sheath. We further propose that neutral sphingomyelinase (SM ase) is one such enzyme, two forms of which have been detected in puri fied myelin. An additional event is accumulation of cholesterol ester, apparently a downstream consequence of cytokine-induced SMase. The re sulting lipid changes are viewed as potentially destabilizing to myeli n, which may render it more vulnerable to attack by invading and resid ent phagocytes.