title: In vitro analysis of cell death of spinal oligodendrocytes in a rat model of HTLV-I infection.
abstract: Local expression of tumor necrosis factor-alpha (TNF-alpha) and apoptotic death of oligodendrocytes (OLGs) appear to be the major pathogenesis of myeloneuropathy in Wistar-King-Aptekman-Hokudai (WKAH) rats with human T lymphocyte virus type I(HTLV-I) infection, HTLV-I-associated myelopathy (HAM) rat disease. In the present study, we examined the sensitivity to TNF-alpha-induced cell death of in vitro-separated OLGs from HILV-I-infected HAM-susceptible WKAH strain rats and HAM-resistant LEW and ACI strain rats. Although the number of non-viable OLGs increased by addition of a recombinant TNF-alpha in a dose-dependent manner, OLGs from the HTLV-I-infected rats, especially from infected WKAH rats, were more susceptible to TNF-alpha than those from uninfected controls. We also examined susceptibility of spinal OLGs from HTLV-I-infected rats against serum cytotoxicity. With serum treatment, the numbers of dead OLGs in HTLV-I-infected rats of all strains examined were significantly higher than those in uninfected controls, especially in WKAH strain rat. The serum cytotoxicity was not due to either serum IgG or complements. In situ detection of DNA fragmentation showed apoptotic death of OLGs by addition of TNF-alpha and serum. To investigate molecular mechanisms of the increasing sensitivity to cytotoxic factors in OLGs of HTLV-I-infected rats, we examined the major protective factor to apoptotic cell death in central nervous system, bcl-2. The expression of bcl-2 mRNA was strongly down-regulated in OLGs of the HTLV-I-infected WKAH rats but not in untreated controls. The collected evidence suggests that the down-regulation of bcl-2 expression in OLGs of HTLV-I-infected rats may increase the susceptibility to TNF-alpha-induced apoptosis of OLGs, resulting in the development of HTLV-I-induced myeloneuropathy in WKAH rats. Serum cytotoxicity may play a role in the late stage of HAM rat disease when the serum insudates into spinal cord with breakdown of the blood-brain barrier.
authors.affiliation: First Department of Pathology, Hokkaido University School of Medicine, Sapporo, Japan.
authors.forename: X
authors.initials: X
authors.lastname: Jiang
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D053938:DNA Fragmentation; D004195:Disease Models, Animal; D015536:Down-Regulation; D019254:Genes, bcl-2 / Q000235:genetics; D007074:Immunoglobulin G / Q000032:analysis; D017628:Microglia / Q000473:pathology; D009836:Oligodendroglia / Q000473:pathology*; D015493:Paraparesis, Tropical Spastic / Q000473:pathology*; D012333:RNA, Messenger; D051381:Rats; D011919:Rats, Inbred Strains; D013116:Spinal Cord / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis*
chemical_list: D007074:Immunoglobulin G; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha