MKK3 signalling plays an essential role in leukocyte-mediated pancreatic injury in the multiple low-dose streptozotocin model
Program in Molecular Medicine
Biochemistry | Cell Biology | Cellular and Molecular Physiology | Molecular Biology
In vitro studies have implicated activation of the p38 mitogen-activated protein kinase (MAPK) signalling pathway in cytokine-mediated pancreatic beta-cell injury. Activation of the p38 MAPK occurs through two different upstream kinases, mitogen-activated protein kinase kinase 3 (MKK3) and MKK6. This study examined the role of MKK3 signalling in an in vivo model of cytokine-dependent pancreatic injury induced by multiple low doses of streptozotocin (MLD-STZ). Groups of wild-type (WT) or Mkk3-/- C57BL/6J mice received 5 daily injections of STZ (40 mg/kg) and were killed on day 5, week 2 or week 4. MLD-STZ in WT mice exhibited two distinct phases of pancreatic damage: islet cell apoptosis (immunostaining for cleaved caspase-3) on day 5 in the absence of leukocyte infiltration, and this was followed by islet inflammation (leukocyte infiltration and cytokine production) and further islet cell apoptosis on day 14 resulting in a loss of insulin-producing beta-cells and an 80% incidence of hyperglycaemia. Mkk3-/- mice were not protected from the initial phase of STZ-induced islet cell apoptosis day 5. However, Mkk3-/- mice were completely protected from the induction of hyperglycaemia. This was attributed to inhibition of leukocyte infiltration, production of pro-inflammatory cytokines and islet cell apoptosis at day 14 of MLD-STZ. In vitro studies showed that cultured islets from Mkk3-/- and WT mice are equally susceptible to STZ and cytokine-induced apoptosis. In conclusion, MKK3 signalling plays an essential role in the development of islet inflammation leading to destruction of beta-cells and hyperglycaemia in MLD-STZ-induced pancreatic injury.
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Citation: Lab Invest. 2008 Apr;88(4):398-407. doi: 10.1038/labinvest.2008.10. Epub 2008 Feb 18. Link to article on publisher's site
Fukuda, Kyoichi; Tesch, Greg H.; Yap, Felicia Y.; Forbes, Josephine M.; Flavell, Richard; Davis, Roger J.; and Nikolic-Paterson, David J., "MKK3 signalling plays an essential role in leukocyte-mediated pancreatic injury in the multiple low-dose streptozotocin model" (2008). Davis Lab. 65.