Inflammatory cell expression of cyclooxygenase-2 in the multiple sclerosis lesion.
Multiple sclerosis (MS) is a progressive immune-mediated disease characterized by the loss of the oligodendrocytes that constitute the myelin sheath. Recent reports show that glutamate-mediated excitotoxic death of oligodendrocytes contributes to pathogenesis in demyelinating disease. A link between the immune-mediated inflammatory response and glutamate-mediated excitotoxicity of oligodendrocytes could involve the interaction of inducible isoforms of nitric oxide synthase (iNOS) and cyclooxygenase (COX-2). Both enzymes are tightly coupled to neuronal excitotoxic death. We examined tissue from two controls and seven MS patients with chronic active lesions to determine the extent of COX-2 and iNOS expression. In contrast to the lack of expression in controls, there was a marked induction of COX-2 in all these MS lesions. COX-2 was frequently expressed in association with iNOS. COX-2 was found in areas that contained catabolites of myelin basic protein, indicating recent demyelination. COX-2 expression was found near damaged oligodendrocytes in cells that expressed the macrophage/microglia marker CD64, indicating that a substantial portion of the COX-2 in the lesions was expressed in immune-derived cells. We discuss these findings in the context of how COX-2 could be coupled with iNOS to contribute to excitotoxic death and damage of oligodendrocytes.
Rose
John W
JW
Neurovirology Research Laboratory VASLCHCS, 500 Foothill Dr. Salt Lake City, UT 84148, USA. jrose@howard.genetics.utah.edu
Hill
Kenneth E
KE
Watt
Hilary E
HE
Carlson
Noel G
NG
D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000378:metabolism; D000328:Adult; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002452:Cell Count / Q000379:methods; D051546:Cyclooxygenase 2; D003711:Demyelinating Diseases / Q000201:enzymology / Q000209:etiology; D005260:Female; D005455:Fluorescent Antibody Technique / Q000379:methods; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000209:etiology; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins; D018613:Microscopy, Confocal / Q000379:methods; D008875:Middle Aged; D008959:Models, Neurological; D009103:Multiple Sclerosis / Q000150:complications / Q000201:enzymology*; D004676:Myelin Basic Protein / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009836:Oligodendroglia / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism*; D017452:Receptors, IgG / Q000378:metabolism; D013194:Staining and Labeling
D007527:Isoenzymes; D008565:Membrane Proteins; D004676:Myelin Basic Protein; D020033:Protein Isoforms; D017452:Receptors, IgG; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases