title: Reciprocal stimulation between TNF-alpha and nitric oxide may exacerbate CNS inflammation in experimental autoimmune encephalomyelitis.
abstract: Nitric oxide (NO) and TNF-alpha are both highly active pleotypic modulators of cell function that are abundantly generated during inflammation. Experiments in animal systems have linked the generation of NO and TNF-alpha to autoimmune pathogenesis, and blockade of either NO or TNF-alpha has been shown to impede disease development. In this study, we show that NO and TNF-alpha can act mutually to stimulate each other's production. While IFN-gamma alone induces NO release from microglia, astrocytes are provoked into significant NO production only by a combination of IFN-gamma and TNF-alpha. Since both TNF-alpha and NO are abundantly generated during T-glial cell interaction, we asked whether and how NO affects TNF-alpha production. Using an in vitro system in which TNF-alpha secretion is induced in MBP-reactive T cells by co-culture with syngeneic astrocytes, we observed that the efficiency of TNF-alpha secretion was markedly increased, in a dose-dependent fashion, by addition of micromolar concentrations of a chemical generator of NO donor, sodium nitroprusside (SNP). Similarly, low concentrations of SNP significantly enhanced the IL-2 dependent growth of MBP-reactive T cells. These results suggest that autoimmune pathogenesis initiated by inflammatory responses within the CNS may result in part from a vicious cycle in which TNF-alpha and NO mutually provoke each other's production.
authors.affiliation: Department of Neurology, University of Alabama at Birmingham, 35294, USA. dsun@uab.edu
authors.forename: D
authors.initials: D
authors.lastname: Sun
authors.forename: C
authors.initials: C
authors.lastname: Coleclough
authors.forename: L
authors.initials: L
authors.lastname: Cao
authors.forename: X
authors.initials: X
authors.lastname: Hu
authors.forename: S
authors.initials: S
authors.lastname: Sun
authors.forename: J N
authors.initials: JN
authors.lastname: Whitaker
mesh_terms: D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001253:Astrocytes / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D002450:Cell Communication / Q000276:immunology; D002540:Cerebral Cortex / Q000166:cytology* / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D004676:Myelin Basic Protein / Q000276:immunology / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000276:immunology* / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000276:immunology / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D007375:Interleukin-1; D004676:Myelin Basic Protein; C110881:S-nitro-N-acetylpenicillamine; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D009569:Nitric Oxide; D007371:Interferon-gamma; D001120:Arginine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D010396:Penicillamine; D019331:NG-Nitroarginine Methyl Ester