title: Differential involvement of IL-6 in the early and late phase of 1-methylnicotinamide (MNA) release in Concanavalin A-induced hepatitis.
abstract: Exogenous 1-methylnicotinamide (MNA) displays anti-inflammatory activity. The aim of this work was to characterize the profile of release of endogenous MNA during the initiation and progression of murine hepatitis induced by Concanavalin A (ConA). In particular we aimed to clarify the role of interleukin-6 (IL-6) as well as the energy state of hepatocytes in MNA release in early and late phases of ConA-induced hepatitis in mice. Hepatitis was induced by ConA in IL-6(+/+) and IL-6(-/-) mice, and various parameters of liver inflammation and injury, as well as the energy state of hepatocytes, were analysed in relation to MNA release. The decrease in ATP/ADP and NADH/NAD ratios, cytokine release (IL-6, IFN-ɤ), acute phase response (e.g. haptoglobin) and liver injury (alanine aminotransaminase, ALT) were all blunted in ConA-induced hepatitis in IL-6(-/-) mice as compared to IL-6(+/+) mice. The release of MNA in response to Con A was also significantly blunted in IL-6(-/-) mice as compared to IL-6(+/+) mice in the early stage of ConA-induced hepatitis. In turn, nicotinamide N-methyltransferase (NNMT) and aldehyde oxidase (AO) activities were blunted in the liver and MNA plasma concentration was elevated to similar degree in the late stage after Concanavalin A in IL-6(+/+) and IL-6(-/-) mice. In conclusion, we demonstrated that in ConA-induced hepatitis, early, but not late MNA release was IL-6-dependent. Our results suggest that in the initiation and early hepatitis, MNA release is linked to the energy deficit/impaired redox status in hepatocytes, while in a later phase, MNA release is rather linked to the systemic inflammation.
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 Experimental Pharmacology, Chair of Pharmacology, Jagiellonian University, Medical College, Kraków, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Jakubowski
authors.affiliation: Department of Pathology, The Children's Memorial Health Institute, Warsaw, Poland.
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Czarnowska
authors.affiliation: Department of Biochemistry, Medical University of Gdańsk, Poland.
authors.forename: Ewa M
authors.initials: EM
authors.lastname: Slominska
authors.affiliation: Department of Biochemistry, Medical University of Gdańsk, Poland.
authors.forename: Ryszard T
authors.initials: RT
authors.lastname: Smolenski
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Kraków, Poland; Department of Pharmacokinetics and Physical Pharmacy, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Szafarz
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Kraków, Poland; Department of Pharmacokinetics and Physical Pharmacy, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Maria
authors.initials: M
authors.lastname: Walczak
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Kraków, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Sitek
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Kraków, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Wojcik
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Kraków, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Jasztal
authors.affiliation: Department of Cardiology, Medical University of Białystok, Poland.
authors.forename: Karol
authors.initials: K
authors.lastname: Kaminski
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Kraków, Poland; Department of Experimental Pharmacology, Chair of Pharmacology, Jagiellonian University, Medical College, Kraków, Poland. Electronic address: stefan.chlopicki@jcet.eu.
authors.forename: Stefan
authors.initials: S
authors.lastname: Chlopicki
mesh_terms: D000210:Acute-Phase Reaction / Q000378:metabolism; D042931:Aldehyde Oxidase / Q000378:metabolism; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics* / Q000378:metabolism*; D003208:Concanavalin A / Q000633:toxicity*; D016207:Cytokines / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects; D006505:Hepatitis / Q000473:pathology; D022781:Hepatocytes / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism; D008111:Liver Function Tests; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000378:metabolism; D050903:Nicotinamide N-Methyltransferase / Q000378:metabolism
chemical_list: D016207:Cytokines; D015850:Interleukin-6; D003208:Concanavalin A; D009536:Niacinamide; D042931:Aldehyde Oxidase; C493760:Aox1 protein, mouse; D050903:Nicotinamide N-Methyltransferase; C494407:Nnmt protein, mouse; C024058:N(1)-methylnicotinamide
keywords: 1-Methylnicotinamide; Concanavalin A; Hepatitis; Interleukin-6