Regulation of Mitogen-Activated Protein Kinases by Sphingolipid Products in Oligodendrocytes

Hida, Hideki; Nagano, Sukehisa; Takeda, Margaret; Soliven, Betty

doi:10.1523/jneurosci.19-17-07458.1999

Cited by 59 publications

(45 citation statements)

References 56 publications

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“…Because we previously found that S1P signaling plays a crucial role in the stimulation of OLG progenitor survival by NT-3 (Saini et al, 2005) and given that most actions of FTY720 are mediated by S1P receptors (Brinkmann and Lynch, 2002), it was of interest to examine the effects of FTY720 on OLG progenitors. Similar to S1P (Hida et al, 1999;Saini et al, 2005), treatment with FTY720 activated ERK1/2 (Fig. 1, A and B).…”

Section: Resultsmentioning

confidence: 67%

The Immunomodulator FTY720 Has a Direct Cytoprotective Effect in Oligodendrocyte Progenitors

Coelho

Payne²,

Bittman³

et al. 2007

The Journal of Pharmacology and Experimental Therapeutics

169

132

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The immunomodulator 2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol (FTY720) has promising therapeutic effects in multiple sclerosis (MS), a degenerative disease in which demyelination of the central nervous system is accompanied by death of oligodendrocytes (OLGs), the myelin-producing cells. In vivo phosphorylation of FTY720 generates an agonist for G protein-coupled receptors for sphingosine-1-phosphate, a lipid mediator that plays a crucial role in the stimulation of OLG survival by neurotrophin-3 (NT-3). The mechanisms underlying the action of FTY720 in MS are not clearly understood, although the effects of this drug in autoimmune diseases are thought to stem from its ability to reduce lymphocyte infiltration and inflammation. Interestingly, we now found that FTY720 also has a direct effect on OLG progenitors. Treatment of these cells with FTY720 causes activation of extracellular signal-regulated kinase 1/2 and Akt, accompanied by protection from apoptosis. However, FTY720 also arrested OLG differentiation. Importantly, this effect was counteracted by NT-3, which not only enhanced the survival of OLG progenitors induced by FTY720 but also stimulated their maturation. Altogether, these observations suggest that in addition to its immunosuppressive functions, FTY720 could also have a beneficial effect in MS by direct action on OLG progenitors. However, the finding that FTY720 blocks the differentiation of these cells raises the question of whether MS therapies with FTY720 should include the use of differentiation-enhancing factors such as NT-3. This approach would ensure both protection of existing OLG progenitor pools against immune-mediated insults as well as stimulation of remyelination by enhancing the maturation of these cells.Multiple sclerosis (MS) is a chronic degenerative and debilitating disease of the central nervous system (CNS) characterized by inflammation and demyelination (McQualter and Bernard, 2007). The pathological hallmarks of MS also include axonal degeneration (Trapp et al., 1999) and death of oligodendrocytes (OLGs) (Barnett and Prineas, 2004;Lucchinetti et al., 2004), the cells that make the myelin membrane in the CNS. Although the cause of MS remains unknown, the presence of serum antibodies against different myelin constituents and the existence of multiple inflammatory foci in brain and spinal cord support the idea of a predominant autoimmune component. For this reason, most therapeutic approaches involve the use of anti-inflammatory drugs and immunosuppressants.2-Amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol (FTY720, also known as Fingolimod), is among the latest immunomodulatory agents under evaluation for the treatment of MS. This synthetic drug was developed by chemical modification of ISP-I (myriocin), a sphingosine-like metabolite produced by the fungus Isaria sinclairii. FTY720 has been shown to prolong allograft survival in different animal models of transplantation (Chiba et al., 1996) and exert a protective effect in animal models of autoimmune diseases (Ma...

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Section: Resultsmentioning

confidence: 67%

The Immunomodulator FTY720 Has a Direct Cytoprotective Effect in Oligodendrocyte Progenitors

Coelho

Payne²,

Bittman³

et al. 2007

The Journal of Pharmacology and Experimental Therapeutics

169

132

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“…In experiments that used ceramide to induce OL apoptosis, p38 was activated (Hida et al, 1999). Furthermore, use of the p38 inhibitor 5B203580 decreased this ceramide-induced apoptosis, while transfection of dominant negative p38 attenuated the apoptotic response.…”

Section: Mature Olmentioning

confidence: 99%

Mitogen‐activated protein kinase signalling in oligodendrocytes: a comparison of primary cultures and CG‐4

Stariha¹,

Kim²

2001

Intl J of Devlp Neuroscience

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Oligodendrocytes play a significant role in the central nervous system, as these cells are responsible for myelinating axons and allowing for the efficient conduction of nerve impulses. Therefore, any understanding we can gain about the functional biology of oligodendrocytes will give us important insights into demyelinating diseases such as multiple sclerosis, where oligodendrocytes and myelin are damaged or destroyed. Currently, much attention has focussed on the role of a family of mitogen-activated protein kinases in OL. This kinase family includes the extracellular signal-regulated protein kinases (ERKs), the stress-activated c-Jun N-terminal kinase (JNK), and the 38 kDa high osmolarity glycerol response kinase (p38). The actions of mitogen-activated protein kinases in oligodendrocytes appear to range from proliferation and cell survival to differentiation and cell death. In the past, studies on oligodendrocytes have been hampered by the difficulties inherent in producing large enough quantities of these cells for experimentation. This problem arises in large part due to the post-mitotic nature of mature oligodendrocytes. Over the years, a cell line known as Central Glia-4 (CG-4) has become a popular oligodendrocyte model due to its potentially unlimited capacity for self-renewal. In this review, we will look at the suitability of the Central Glia-4 cell line as an oligodendrocyte model, specifically in respect to studies on mitogen-activated protein kinase signalling in oligodendrocytes.

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“…3A and 3B). A number of studies have reported that p38 MAPK is involved in the mediation of ceramide-induced cell death [8][9][30][31] . Nevertheless, no report supports the role of p38 MAPK in the mediation of ceramide-induced apoptosis [11][12] .…”

Section: Discussionmentioning

confidence: 99%

“…The implications of JNK and p38 MAPK in ceramide-induced cell death in various cell types have been revealed by pharmacological and molecular assays [8][9][10] . However, it has also been demonstrated that p38 MAPK may not be essential for ceramide-induced cell death in U937 and MC/9 cells [11][12] .…”

Section: Introductionmentioning

confidence: 99%

Potential Mechanisms Involved in Ceramide-induced Apoptosis in Human Colon Cancer HT29 Cells

Wang

2009

Biomedical and Environmental Sciences

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Regulation of Mitogen-Activated Protein Kinases by Sphingolipid Products in Oligodendrocytes

Cited by 59 publications

References 56 publications

The Immunomodulator FTY720 Has a Direct Cytoprotective Effect in Oligodendrocyte Progenitors

The Immunomodulator FTY720 Has a Direct Cytoprotective Effect in Oligodendrocyte Progenitors

Mitogen‐activated protein kinase signalling in oligodendrocytes: a comparison of primary cultures and CG‐4

Potential Mechanisms Involved in Ceramide-induced Apoptosis in Human Colon Cancer HT29 Cells

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