title: 1-Methylnicotinamide protects against liver injury induced by concanavalin A via a prostacyclin-dependent mechanism: A possible involvement of IL-4 and TNF-α.
abstract: We have recently demonstrated that concanavalin A (Con A)-induced hepatitis is associated with the release of endogenous 1-methylnicotinamide (MNA). Here we study the mechanism by which exogenous MNA alleviates Con A-induced liver inflammation and injury in vivo. The involvement of prostacyclin (PGI2) in hepatoprotective action of MNA (30-100 mg kg(-1); i.v.) was studied by the use of IP receptor antagonist RO3244794 (10 mg kg(-1); p.o.) given prior to Con A (5-20 mg kg(-1); i.v.). Liver damage was assessed by measurements of: liver specific transaminases in plasma (alanine aminotransferase; aspartate aminotransferase); cytokines release (IL-4, IFN-γ and TNF-α); liver histopathology; and 24h survival rates. Additionally, the effect of a stable analog of prostacyclin (carbaprostacyclin) on IL-4, IFN-γ and TNF-α production by isolated spleen lymphocytes in response to Con A was analyzed. MNA diminished Con A-induced rise in liver specific transaminases, alleviated histopathological injury and improved 24h survival rates, the latter effect in a degree comparable with the pretreatment of animals with dexamethasone (0.5 mg kg(-1); i.p.). MNA inhibited also a rise in IL-4 and TNF-α concentration in plasma measured 2 h after Con A administration, while IFN-γ was less affected. The effects of MNA were reversed by pretreatment with IP antagonist RO3244794. In isolated spleen lymphocytes, carbaprostacyclin profoundly decreased production of IL-4, the effect on TNF-α was modest with no effect on IFN-γ production. In conclusion, MNA attenuated Con A-induced hepatitis by a prostacyclin-dependent mechanism involving the inhibition of lymphocytes-derived IL-4 and the inhibition of Kuppfer-cells derived TNF-α.
authors.affiliation: Department of Experimental Pharmacology, Chair of Pharmacology, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Jakubowski
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Kraków, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Sternak
authors.affiliation: Department of Medical Education, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Konrad
authors.initials: K
authors.lastname: Jablonski
authors.affiliation: Chair of Immunology Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Ciszek-Lenda
authors.affiliation: Chair of Immunology Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Janusz
authors.initials: J
authors.lastname: Marcinkiewicz
authors.affiliation: Department of Experimental Pharmacology, Chair of Pharmacology, Jagiellonian University Medical College, Kraków, Poland; Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Kraków, Poland. Electronic address: stefan.chlopicki@jcet.eu.
authors.forename: Stefan
authors.initials: S
authors.lastname: Chlopicki
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000008:administration & dosage; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000276:immunology; D003208:Concanavalin A / Q000378:metabolism; D003907:Dexamethasone / Q000008:administration & dosage; D011464:Epoprostenol / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009536:Niacinamide / Q000008:administration & dosage*; D011422:Propionates / Q000008:administration & dosage; D044006:Receptors, Epoprostenol / Q000037:antagonists & inhibitors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D001572:Benzofurans; D011422:Propionates; C515593:RO3244794; D044006:Receptors, Epoprostenol; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D015847:Interleukin-4; D009536:Niacinamide; D003907:Dexamethasone; D011464:Epoprostenol
keywords: 1-Methylnicotynamide; Concanavalin A; IL-4; Murine hepatic injury; Prostacyclin