Role of neuronal interferon-gamma in the development of myelopathy in rats infected with human T-cell leukemia virus type 1.
Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of not only adult T-cell leukemia but also HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Among the rat strains infected with HTLV-1, chronic progressive myelopathy, named HAM rat disease, occurs exclusively in WKAH rats. In the present study, we found that HTLV-1 infection induces interferon (IFN)-gamma production in the spinal cords of HAM-resistant strains but not in those of WKAH rats. Neurons were the major cells that produced IFN-gamma in HTLV-1-infected, HAM-resistant strains. Administration of IFN-gamma suppressed expression of pX, the gene critically involved in the onset of HAM rat disease, in an HTLV-1-immortalized rat T-cell line, indicating that IFN-gamma protects against the development of HAM rat disease. The inability of WKAH spinal cord neurons to produce IFN-gamma after infection appeared to stem from defects in signaling through the interleukin (IL)-12 receptor. Specifically, WKAH-derived spinal cord cells were unable to up-regulate the IL-12 receptor beta2 gene in response to IL-12 stimulation. We suggest that the failure of spinal cord neurons to produce IFN-gamma through the IL-12 pathway is involved in the development of HAM rat disease.
Miyatake
Yukiko
Y
Department of Pathology/Pathophysiology, Division of Pathophysiological Science, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo 060-8638, Japan.
Ikeda
Hitoshi
H
Ishizu
Akihiro
A
Baba
Tomohisa
T
Ichihashi
Toru
T
Suzuki
Akira
A
Tomaru
Utano
U
Kasahara
Masanori
M
Yoshiki
Takashi
T
D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression / Q000502:physiology; D016355:Genes, pX; D015490:HTLV-I Infections / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D015368:Human T-lymphotropic virus 1; D007371:Interferon-gamma / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000378:metabolism*; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011919:Rats, Inbred Strains; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000235:genetics; D053707:Receptors, Interleukin-12; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013116:Spinal Cord / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D013118:Spinal Cord Diseases / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D013601:T-Lymphocytes / Q000378:metabolism / Q000821:virology
C508439:IL12RB2 protein, human; C508444:Il12rb2 protein, rat; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D018664:Interleukin-12; D007371:Interferon-gamma