MKK3 signalling plays an essential role in leukocyte-mediated pancreatic injury in the multiple low-dose streptozotocin model
| Autor: | Kyoichi Fukuda, Richard A. Flavell, David J. Nikolic-Paterson, Greg H. Tesch, Roger J. Davis, Felicia Y. T. Yap, Josephine M. Forbes |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Male
MAPK/ERK pathway medicine.medical_specialty Programmed cell death endocrine system diseases MAP Kinase Signaling System MAP Kinase Kinase 3 T-Lymphocytes p38 mitogen-activated protein kinases medicine.medical_treatment Apoptosis Biology Diabetes Mellitus Experimental Pathology and Forensic Medicine Mice Insulin-Secreting Cells Internal medicine medicine Animals Molecular Biology Mice Knockout geography geography.geographical_feature_category Kinase Cell Biology Streptozotocin Islet Mice Inbred C57BL Endocrinology Cytokine Pancreatitis Cytokines medicine.drug |
| Zdroj: | Laboratory Investigation. 88:398-407 |
| ISSN: | 0023-6837 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|