MKK3 signalling plays an essential role in leukocyte-mediated pancreatic injury in the multiple low-dose streptozotocin model

Fukuda, Kyoichi, Tesch, Greg H., Yap, Felicia Y., Forbes, Josephine M., Flavell, Richard A., Davis, Roger J. and Nikolic-Paterson, David J. (2008) MKK3 signalling plays an essential role in leukocyte-mediated pancreatic injury in the multiple low-dose streptozotocin model. Laboratory Investigation, 88 4: 398-407. doi:10.1038/labinvest.2008.10


Author Fukuda, Kyoichi
Tesch, Greg H.
Yap, Felicia Y.
Forbes, Josephine M.
Flavell, Richard A.
Davis, Roger J.
Nikolic-Paterson, David J.
Title MKK3 signalling plays an essential role in leukocyte-mediated pancreatic injury in the multiple low-dose streptozotocin model
Journal name Laboratory Investigation   Check publisher's open access policy
ISSN 0023-6837
1530-0307
Publication date 2008-04-01
Sub-type Article (original research)
DOI 10.1038/labinvest.2008.10
Open Access Status Not yet assessed
Volume 88
Issue 4
Start page 398
End page 407
Total pages 10
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Formatted abstract
In vitro studies have implicated activation of the p38 mitogen-activated protein kinase (MAPK) signalling pathway in cytokine-mediated pancreatic β-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 β-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 β-cells and hyperglycaemia in MLD-STZ-induced pancreatic injury.
Keyword β-cell
Apoptosis
Cytokine
Hyperglycaemia
Macrophage
P38 MAPK
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
 
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