Tumor necrosis factor-alpha regulation of insulin-like growth factor-I, type 1 IGF receptor, and IGF binding protein expression in cerebellum of transgenic mice.
Tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine, has been implicated in the pathogenesis of several disorders and injuries in the central nervous system (CNS). Unlike IGF-I, which promotes CNS growth, TNF-alpha causes brain growth retardation and neural damage. Recently TNF-alpha has been shown to inhibit IGF-I signaling and actions in non-neural tissue. To investigate whether TNF-alpha deleteriously influences brain growth by altering the IGF-I system in vivo, we examined the expression of IGF-I, the type 1 IGF receptor (IGF1R) and IGF binding proteins (IGFBPs) in the brain of transgenic (Tg) mice with murine TNF-alpha overexpression. We show that overexpression of TNF-alpha reduces the weights of whole brain and all brain regions examined during development. In adult TNF-alpha Tg mice, cerebellum (CB) exhibited the greatest reduction in weight among the five brain regions examined, being approximately 77% of that in wild-type (WT) mice. IGF-I abundance was decreased in the CB, as well as in cerebral cortex and diencephalon, of TNF-alpha Tg mice. When compared to those in WT mice, CB IGF-I abundance in Tg mice was reduced by approximately 35%, approximately 45%, and approximately 40% at 2, 6, and 9 weeks of age, respectively. Of the IGFBPs studied the abundance of IGFBP-3 and IGFBP-4 was increased by 2-3.7-fold, and the abundance of IGFBP-5 was decreased by approximately 3-fold (as judged by Western immunoblot analysis). Histological analysis and immunocytochemical staining confirmed that TNF-alpha specifically increases IGFBP-3 and IGFBP-4 immunoreactivity, as well as that of the IGF1R, in radial glial and Purkinje cells. In addition, TNF-alpha alters CB cytoarchitecture, apparently by influencing granule cell migration. Our data indicate that TNF-alpha alters the expression of IGF-I system proteins in vivo, and suggest that altered expression of IGF-I system proteins may in part explain TNF-alpha deleterious actions on brain growth.
Ye
Ping
P
Division of Endocrinology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. ping_ye@med.unc.edu
Price
Wayne
W
Kassiotis
George
G
Kollias
George
G
D'Ercole
A Joseph
AJ
D000367:Age Factors; D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D002531:Cerebellum / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D007150:Immunohistochemistry; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects / Q000235:genetics; D011689:Purkinje Cells / Q000166:cytology / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology
D018969:Insulin-Like Growth Factor Binding Proteins; D014409:Tumor Necrosis Factor-alpha; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1