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.
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.
Hirasawa
K
K
Laboratory of Viral and Immunopathogenesis of Diabetes, Julia McFarlane Diabetes Research Centre, Department of Microbiology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada.
Jun
H S
HS
Han
H S
HS
Zhang
M L
ML
Hollenberg
M D
MD
Yoon
J W
JW
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
D004791:Enzyme Inhibitors; D020032:Tyrphostins; C069028:AG 127; C098981:AG 556; D009569:Nitric Oxide; D011505:Protein-Tyrosine Kinases