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Abstract
Woo-Yong Lee1, Marko Salmi2,3,4, Margaret Kelly1, Sirpa Jalkanen2,4, Paul Kubes1,*
1 Immunology Research Group, Department of Physiology and Pharmacology, Faculty of Medicine, University of Calgary, Alberta T2N 4N1, Canada
2 MediCity Research Laboratory, University of Turku, Turku, Finland
3 Department of Medical Biochemistry and Genetic, University of Turku, Turku, Finland
4 National Institute of Health and Welfare; Tykistokatu, Turku, Finland
*Corresponding author
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/hep.26469
Abstract
Hepatitis induced by concanavalin A (Con A) in mice is well-known to be a T lymphocyte-mediated injury. It has been reported that Th1 and Th2 lymphocytes use α4 integrin and vascular adhesion protein (VAP)-1, respectively, to adhere within the hepatic sinusoids. Therefore, we investigated whether inhibition of these molecules ameliorates or worsens the Con A-induced hepatic injury in vivo. Vehicle or antibody to α4 integrin (PS/2, 100 μg) or VAP-1 (cocktail of 7-88 and 7-106, 50 μg each) was intravenously administered 30 min before Con A administration. In control mice Con A markedly increased the serum ALT level in a dose dependent manner, and induced a massive infiltration of CD3, particularly IL-4 producing CD4 T cells and liver injury. Both parameters were reduced by anti-VAP-1 antibody despite antibody only blocking the adhesion not amine oxidase activity of VAP-1. Both activities of VAP-1 were eliminated in VAP-1 deficient mice and both Con A induced liver injury and CD4 T cell infiltration were eradicated. In contrast to anti-VAP-1, anti-α4 integrin antibody reduced IFN-γ producing CD3 T cells but this worsened Con A hepatitis suggesting inhibition of a suppressor cell. Con A induced the recruitment of CD49d+ monocytic myeloid derived suppressor cells (MDSCs) and regulatory T cells (Tregs) into the liver. Anti-α4 integrin dramatically blocked the influx of MDSCs but not Tregs.
Conclusions: Our findings show that VAP-1 and α4 integrin have opposing effects in the Con A-induced hepatic injury, which is associated with blocking the recruitment of CD4 lymphocytes and monocytic MDSCs, respectively. Moreover these data provide the rationale for a potential therapeutic approach to target adhesion molecules in autoimmune hepatitis. (HEPATOLOGY 2013.)
Keywords: Adhesion molecules; autoimmune hepatitis; T lymphocytes; myeloid derived suppressor cells; regulatory T cells
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