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

  title={Cytokines, Signal Transduction, and Inflammatory Demyelination: Review and Hypothesis},
  author={Robert W. Ledeen and Goutam Chakraborty},
  journal={Neurochemical Research},
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-α (TNFα) and lymphotoxin (LT). Many studies have shown these and… 
Modulation of remyelination by adaptive inflammation and electrical stimulation
The induction of experimental autoimmune encephalomyelitis by immunization with MOG35-55 peptide in a model of Cuprizone-induced demyelination led to increased infiltration of inflammatory mediators like T cells, B cells, NK cells, granulocytes and inflammatory monocytes and subsequent increased axonal damage.
Oligodendrocyte cell death in pathogenesis of multiple sclerosis: Protection of oligodendrocytes from apoptosis by complement.
By inducing EAE in C5-deficient mice, it is shown that complement C5 promotes axon preservation and new myelin formation, which protect OLGs from apoptosis, and indicates that activated complement C4b-9 plays a proinflammatory role in acute MS but may also protect OLG death in chronic MS.
Cytokine toxicity to oligodendrocyte precursors is mediated by iron
Insight is provided into the controversy regarding the toxicity of cytokines to oligodendrocytes by revealing that iron status of these cells will significantly impact the outcome of cytokine treatment, and mitochondrial dysfunction may underlie the iron‐mediated cytokine toxicity.
Association Between Multiple Sclerosis and Alcohol Consumption: One Hypothesis Based on Immunological Studies
Investigation through previous experimental studies with regard to possible immunological mechanisms that can be mediated by alcohol showed that although consumption of this substance may lead to some damages to brain tissues, ethanol can also induce immunological processes that cause reduction of inflammatory conditions and promotion of anti-inflammatory immune responses which lead to improvement of symptoms of MS patients.
A study of microglial metabotropic glutamate receptor modulation of inflammation
The effects of microglia exposure to myelin were investigated and demonstrated that myelin induced microglial activation, upregulation of iNOS expression, and increased TNFa and nitrite release, suggesting that modulation ofmicroglial mGluRs may be of therapeutic benefit in MS.


Immunologic Mechanisms and Therapy in Multiple Sclerosis
The mechanism(s) by which the inflammation is initiated and maintained, both in this disease and in fact in all of the presumed Tcell mediated autoimmune diseases in humans, has been difficult to define.
Mechanisms of Immune Injury in Multiple Sclerosis
The results strongly support the conclusion that proinflammatory cytokines are major mediators of tissue damage, through the activation of inflammatory cells and resident glial cells.
Inflammation in EAE: Role of chemokine/cytokine expression by resident and infiltrating cells
The events that occur during the inflammatory process in EAE are summarized and the roles of cytokine and chemokine expression by the resident and infiltrating cells participating in the process are discussed.
Tumor necrosis factor mediates myelin and oligodendrocyte damage in vitro
It appears that a physiological (not structural) demyelination occurs initially without overt destruction of the myelin sheath, relevant to the evolution of the multiple sclerosis plaque: dysfunction of ionic channels might contribute to the eventual demise of oligodendrocytes and axons in the longstanding lesion.
TNF‐α‐ and IFN‐γ‐mediated signal transduction pathways: effects on glial cell gene expression and function
  • E. Benveniste, D. Benos
  • Biology
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology
  • 1995
The biological role of two cytokines, namely: tumor necrosis factor α (TNF‐α), and interferon‐gamma (IFN‐γ), in the progression of neurologic disorders such as multiple sclerosis (MS) and AIDS dementia complex (ADC), are focused on, with an emphasis on cytokine effects on glial cells.
Differential Oligodendroglial Expression of the Tumor Necrosis Factor Receptors In Vivo and In Vitro
The inducibility of TNF‐RI may explain the differences in oligodendrocyte cell death reported in various experimental conditions and in the pathology of MS lesions.
Are current immunological concepts of multiple sclerosis reflected by the immunopathology of its lesions?
It appears unlikely, that myelin basic protein is a major candidate for a pathogenetic role in MS, but it is likely that antibodies directed against surface components of myelin sheaths are at least one factor involved in the demyelinating process.
Review: cytokines and the pathogenesis of multiple sclerosis
Perivascular accumulation of mononuclear cells (MNCs) in the central nervous system (CNS) and high levels of myelin autoantigen‐reactive T cells in blood and further enriched in cerebrospinal fluid