IngentaConnect Cytokines, Signal Transduction, and Inflammatory Demyelination: R...

Authors: Ledeen R.W.¹; Chakraborty G.²

Source: Neurochemical Research, Volume 23, Number 3, March 1998 , pp. 277-289(13)

Publisher: Springer

Abstract:

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 tissue/cell culture systems. Myelin and oligodendrocyte (OL) destruction occur in cultured preparations subjected to cytokines such as tumor necrosis factor- alpha (TNF alpha ) and lymphotoxin (LT). Many studies have shown these and other cytokines to be elevated at lesion sites and in the CSF of multiple sclerosis (MS) patients, with similar findings in animal models. Some variability in the nature of MS lesion formation has been reported, both OLs and myelin being primary targets. To account for myelin destruction in the presence of apparently functional OLs we hypothesize that cytokines such as TNF alpha and LT alpha contribute to myelin damage through triggering of specific reactions within the myelin sheath. We further propose that neutral sphingomyelinase (SMase) is one such enzyme, two forms of which have been detected in purified myelin. An additional event is accumulation of cholesterol ester, apparently a downstream consequence of cytokine-induced SMase. The resulting lipid changes are viewed as potentially destabilizing to myelin, which may render it more vulnerable to attack by invading and resident phagocytes.

Keywords: Myelin; demyelination; autoimmune demyelination; cytokine; tumor necrosis factor; lymphotoxin; interleukin; interferon; multiple sclerosis; EAE; cholesterol esters; signal transduction; signalling reactions in myelin

Language: English

Document Type: Research article

Affiliations: 1: Department of Neurosciences, New Jersey Medical School, UMDNJ 185 South Orange Ave., Newark, NJ 07103. ledeenro@umdnj.edu 2: Department of Neurosciences, New Jersey Medical School, UMDNJ 185 South Orange Ave., Newark, NJ 07103

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Cytokines, Signal Transduction, and Inflammatory Demyelination: Review and Hypothesis