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.
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Authors | K Hirasawa, H S Jun, H S Han, M L Zhang, M D Hollenberg, J W Yoon |
Journal | Journal of virology
(J Virol)
Vol. 73
Issue 10
Pg. 8541-8
(Oct 1999)
ISSN: 0022-538X [Print] United States |
PMID | 10482607
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Enzyme Inhibitors
- Tyrphostins
- AG 127
- AG 556
- Nitric Oxide
- Protein-Tyrosine Kinases
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Topics |
- Animals
- Cardiovirus Infections
(metabolism, prevention & control)
- Cells, Cultured
- Diabetes Mellitus, Type 1
(metabolism, prevention & control, virology)
- Enzyme Inhibitors
(pharmacology, therapeutic use)
- Macrophage Activation
(drug effects)
- Macrophages, Peritoneal
(metabolism, virology)
- Maus Elberfeld virus
- Mice
- Mice, Inbred DBA
- Nitric Oxide
(antagonists & inhibitors, metabolism)
- Protein-Tyrosine Kinases
(antagonists & inhibitors, metabolism)
- Signal Transduction
(drug effects)
- Tyrphostins
(pharmacology, therapeutic use)
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