title: Prevention of encephalomyocarditis virus-induced diabetes in mice by inhibition of the tyrosine kinase signalling pathway and subsequent suppression of nitric oxide production in macrophages.
abstract: Macrophages comprise the major population of cells infiltrating pancreatic islets during the early stages of infection in DBA/2 mice by the D variant of encephalomyocarditis virus (EMC-D virus). Inactivation of macrophages prior to viral infection almost completely prevents EMC-D virus-induced diabetes. This investigation was initiated to determine whether a tyrosine kinase signalling pathway might be involved in the activation of macrophages by EMC-D virus infection and whether tyrosine kinase inhibitors might, therefore, abrogate EMC-D virus-induced diabetes in vivo. When isolated macrophages were infected with EMC-D virus, inducible nitric oxide synthase mRNA was expressed and nitric oxide was subsequently produced. Treatment of macrophages with the tyrosine kinase inhibitor tyrphostin AG126, but not tyrphostin AG556, prior to EMC-D virus infection blocked the production of nitric oxide. The infection of macrophages with EMC-D virus also resulted in the activation of the mitogen-activated protein kinases (MAPKs) p42(MAPK/ERK2)/p44(MAPK/ERK1), p38(MAPK), and p46/p54(JNK). In accord with the greater potency of AG126 than of AG556 in blocking EMC-D virus-mediated macrophage activation, the incidence of diabetes in EMC-D virus-infected mice treated with AG126 (25%) was much lower than that in AG556-treated (75%) or vehicle-treated (88%) control mice. We conclude that EMC-D virus-induced activation of macrophages resulting in macrophage-mediated beta-cell destruction can be prevented by the inhibition of a tyrosine kinase signalling pathway involved in macrophage activation.
authors.affiliation: Laboratory of Viral and Immunopathogenesis of Diabetes, Julia McFarlane Diabetes Research Centre, Department of Microbiology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Hirasawa
authors.forename: H S
authors.initials: HS
authors.lastname: Jun
authors.forename: H S
authors.initials: HS
authors.lastname: Han
authors.forename: M L
authors.initials: ML
authors.lastname: Zhang
authors.forename: M D
authors.initials: MD
authors.lastname: Hollenberg
authors.forename: J W
authors.initials: JW
authors.lastname: Yoon
mesh_terms: D000818:Animals; D018188:Cardiovirus Infections / Q000378:metabolism* / Q000517:prevention & control; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000517:prevention & control / Q000821:virology*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D008262:Macrophage Activation / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000378:metabolism / Q000821:virology*; D004680:Maus Elberfeld virus; D051379:Mice; D008811:Mice, Inbred DBA; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020032:Tyrphostins / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D004791:Enzyme Inhibitors; D020032:Tyrphostins; C069028:AG 127; C098981:AG 556; D009569:Nitric Oxide; D011505:Protein-Tyrosine Kinases