title: Differential tumor necrosis factor alpha expression by astrocytes from experimental allergic encephalomyelitis-susceptible and -resistant rat strains.
abstract: There is evidence that the cytokine tumor necrosis factor alpha (TNF-alpha) contributes to the pathogenesis of neurological autoimmune diseases such as multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE). TNF-alpha exerts damaging effects on oligodendrocytes, the myelin-producing cell of the central nervous system (CNS), and myelin itself. We have recently demonstrated TNF-alpha expression from astrocytes induced by lipopolysaccharide (LPS), interferon gamma (IFN-gamma), and interleukin 1 beta (IL-1 beta). Astrocytes secrete TNF-alpha in response to LPS alone, and can be primed by IFN-gamma to enhance LPS-induced TNF-alpha production. IFN-gamma and IL-1 beta, cytokines known to be present in the CNS during neurological disease states, do not induce TNF-alpha production alone, but act synergistically to stimulate astrocyte TNF-alpha expression. Inbred Lewis and Brown-Norway (BN) rats differ in genetic susceptibility to EAE, which is controlled in part by major histocompatibility complex (MHC) genes. We examined TNF-alpha gene expression by astrocytes derived from BN rats (resistant to EAE) and Lewis rats (highly susceptible). Astrocytes from BN rats express TNF-alpha mRNA and protein in response to LPS alone, yet IFN-gamma does not significantly enhance LPS-induced TNF-alpha expression, nor do they express appreciable TNF-alpha in response to the combined stimuli of IFN-gamma/IL-1 beta. In contrast, astrocytes from Lewis rats express low levels of TNF-alpha mRNA and protein in response to LPS, and are extremely responsive to the priming effect of IFN-gamma for subsequent TNF-alpha gene expression. Also, Lewis astrocytes produce TNF-alpha in response to IFN-gamma/IL-1 beta. The differential TNF-alpha production by astrocytes from BN and Lewis strains is not due to the suppressive effect of prostaglandins, because the addition of indomethacin does not alter the differential pattern of TNF-alpha expression. Furthermore, Lewis and BN astrocytes produce another cytokine, IL-6, in response to LPS, IFN-gamma, and IL-1 beta in a comparable fashion. Peritoneal macrophages and neonatal microglia from Lewis and BN rats are responsive to both LPS and IFN-gamma priming signals for subsequent TNF-alpha production, suggesting that differential TNF-alpha expression by the astrocyte is cell type specific. Taken together, these results suggest that differential TNF-alpha gene expression in response to LPS and IFN-gamma is strain and cell specific, and reflects both transcriptional and post-transcriptional control mechanisms.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Department of Cell Biology, University of Alabama, Birmingham 35294.
authors.forename: I Y
authors.initials: IY
authors.lastname: Chung
authors.forename: J G
authors.initials: JG
authors.lastname: Norris
authors.forename: E N
authors.initials: EN
authors.lastname: Benveniste
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000502:physiology*; D001483:Base Sequence; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology*; D007213:Indomethacin / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism; D008969:Molecular Sequence Data; D009841:Oligonucleotides / Q000737:chemistry; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew / Q000502:physiology; D011919:Rats, Inbred Strains / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009841:Oligonucleotides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D007213:Indomethacin