15d-PGJ2 induces apoptosis of mouse oligodendrocyte precursor cells
Journal of Neuroinflammation
15d-PGJ2 induces apoptosis of mouse oligodendrocyte precursor cells
Zhongmin Xiang 0
Tong Lin 0
Steven A Reeves 0
0 Address: CNS Signaling Laboratory, MassGeneral Institute for Neurodegenerative Disease (MIND), Massachusetts General Hospital, Harvard Medical School , 114 16th Street, Charlestown, MA 02129 , USA
Background: Prostaglandin (PG) production is associated with inflammation, a major feature in multiple sclerosis (MS) that is characterized by the loss of myelinating oligodendrocytes in the CNS. While PGs have been shown to have relevance in MS, it has not been determined whether PGs have a direct effect on cells within the oligodendrocyte lineage. Methods: Undifferentiated or differentiated mouse oligodendrocyte precursor (mOP) cells were treated with PGE2, PGF2α, PGD2 or 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2). Cell growth and survival following treatment were examined using cytotoxicity assays and apoptosis criteria. The membrane receptors for PGD2 and the nuclear receptor peroxisome proliferator-activated receptor (PPAR)γ, as well as reactive oxygen species (ROS) in the death mechanism were examined. Results: PGE2 and PGF2α had minimal effects on the growth and survival of mOP cells. In contrast, PGD2 and 15d-PGJ2 induced apoptosis of undifferentiated mOP cells at relatively low micromolar concentrations. 15d-PGJ2 was less toxic to differentiated mOP cells. Apoptosis was independent of membrane receptors for PGD2 and the nuclear receptor PPARγ. The cytotoxicity of 15d-PGJ2 was associated with the production of ROS and was inversely related to intracellular glutathione (GSH) levels. However, the cytotoxicity of 15d-PGJ2 was not decreased by the free radical scavengers ascorbic acid or α-tocopherol. Conclusion: Taken together, these results demonstrated that 15d-PGJ2 is toxic to early stage OP cells, suggesting that 15d-PGJ2 may represent a deleterious factor in the natural remyelination process in MS.
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Background
Prostaglandin (PG)s are a group of 20-carbon fatty acids
derived from membrane lipids. By sequential enzymatic
reactions of phospholipase A2 (PLA2), housekeeping
cyclooxygenase (COX)-1 or inducible COX-2, PGH2 is
generated and then converted to PGE2, PGD2, PGF2α,
PGI2 (prostacyclin) and TXA2 (thromboxane A2) by their
respective PG isomerases [1]. For example, PGH2 is first
converted to PGD2 by lipocalin-type PGD2 synthase
(LPGDS) or hematopoietic (H)-PGDS, which then
undergoes sequential non-enzymatic dehydration reactions to
form 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2). PGs generally act
through membrane-bound G-protein coupled PG
receptors with the exception of 15d-PGJ2, which has no
defined membrane receptor, although reported to be an
activator of the PGD2 receptor DP2 [2]. Instead, 15d-PGJ2
is a natural ligand for the nuclear receptor peroxisome
proliferator-activated receptor (PPAR)γ [3], which has a
major role in the regulation of proliferation,
differentiation and lipid metabolism [4,5]. Moreover, 15d-PGJ2 has
been shown to induce apoptosis of cultured cortical
neurons [6,7], endothelial cells [8], hepatic myofibroblasts
[9], granulocytes [10] and cancer cells [11], through both
PPARγ-dependent and PPARγ-independent mechanisms
[9,10].
Mounting evidence suggests that PGs play important roles
in neuroinflammatory diseases such as multiple sclerosis
(MS), an autoimmune disease of the central nervous
system (CNS) in which T- and B cells attack components of
the myelin sheath leading to loss of myelin as well as
myelinating oligodendrocytes [12-14]. As a natural repair
mechanism, oligodendrocyte precursor (OP) cells
proliferate and differentiate within the demyelination sites to
replenish the lost myelinating oligodendrocytes [15,16].
In patients with MS and in the experimental autoimmune
encephalomyelitis (EAE) rodent model, the
demyelination foci are typically characterized by inflammatory
infiltrates containing myelin-specific T- and B cells, and
activated microglia and astrocytes [12,14,17-19]. These
inflammatory cells are known to secrete cytotoxic
cytokines such as TNFα and interleukin (IL)-6 [12,20], as
well as PGs such as PGE2, PGD2 and PGF2α [21-23].
Bacterial lipopolysaccharide (LPS), which is a potent
proinflammatory factor that induces abundant PGD2 or
15dPGJ2 production in microglia cultures [24,25], and in the
CSF and spinal cord following systemic administration
[26,27]. In MS demyelination foci, gene expression of PG
related enzymes such as PLA2 [28], COX-2 [29] and
LPGDS [30] are up-regulated. Increased L-PGDS in
perineuronal oligodendrocytes and H-PGDS in microglia are
also observed in the mouse twitcher demyelination model
[31,32]. Additional evidence has shown that H-PGDS is
increased in activated T helper (Th)2 cells in vitro [23].
While these findings suggest that OP cells are exposed to
a PG-rich environment, little is known regarding the effect
these PGs have on OP cells.
In this study, we examined the effect of PGs on mouse OP
(mOP) ce (...truncated)