PMID- 21116608
OWN - NLM
STAT- MEDLINE
DCOM- 20110525
LR  - 20211020
IS  - 1432-0428 (Electronic)
IS  - 0012-186X (Linking)
VI  - 54
IP  - 3
DP  - 2011 Mar
TI  - TNF-alpha acutely upregulates amylin expression in murine pancreatic beta cells.
PG  - 617-26
LID - 10.1007/s00125-010-1972-9 [doi]
AB  - AIMS/HYPOTHESIS: Amylin, a secretory protein mainly produced by pancreatic beta 
      cells, is elevated in the circulation of patients with diseases related to acute 
      and chronic inflammation, including acute pancreatitis, pancreas graft rejection, 
      obesity and insulin resistance. TNF-alpha is involved in these disorders. We 
      investigated the effect of TNF-alpha on amylin levels and the underlying mechanisms, 
      using murine pancreatic beta cell line MIN6 and pancreatic islets. METHODS: 
      Amylin, proinsulin and prohormone convertase 1/3, 2 (Pc1/3, Pc2 [also known as 
      Pcsk1/3 and Pcsk2, respectively]) mRNA levels, and amylin promoter and nuclear 
      factor kappaB (NF-kappaB) activation were examined by real-time PCR and luciferase 
      reporter assay, respectively. Amylin protein level and mitogen-activated protein 
      kinase phosphorylation were detected by western blot. Activator protein 1 (AP1) 
      activation was examined by electrophoretic mobility shift assay (EMSA). RESULTS: 
      TNF-alpha acutely induced amylin expression at the transcriptional level and 
      increased proamylin and the intermediate form of amylin in MIN6 cells and islets. 
      However, it had no effect on proinsulin, Pc1/3 and Pc2 expression. Studies with 
      (1) MIN6 cells treated with inhibitors of MEK1/2, c-Jun-N-terminal kinase (JNK) 
      or protein kinase Czeta (PKC(zeta)), (2) MIN6 cells expressing a c-Jun-dominant 
      negative construct and (3) islets from Fos knockout mice demonstrated that TNF-alpha 
      induced amylin expression through the PKC(zeta)-extracellular signal-regulated 
      kinase (ERK)/JNK pathways. EMSA showed that (PKC(zeta)), JNK and ERK1/2 were 
      involved in TNF-alpha-induced AP1 activation, suggesting that TNF-alpha induces murine 
      amylin expression through the (PKC(zeta)) - ERK1/2 - AP and PKC(zeta) - JNK - AP1 
      pathways. Further studies showed that TNF-alpha also induced murine amylin expression 
      through the phosphatidylinositol 3 kinase-NF-kappaB signalling pathway and enhanced 
      human amylin promoter activation through NF-kappaB and AP1. 
      CONCLUSIONS/INTERPRETATION: TNF-alpha acutely induces amylin gene expression in beta 
      cells through multiple signalling pathways, possibly contributing to amylin 
      elevation in acute inflammation-related pancreatic disorders.
FAU - Cai, K
AU  - Cai K
AD  - Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, 
      Shanghai Institutes for Biological Sciences, Graduate School of the Chinese 
      Academy of Sciences, Shanghai, People's Republic of China.
FAU - Qi, D
AU  - Qi D
FAU - Wang, O
AU  - Wang O
FAU - Chen, J
AU  - Chen J
FAU - Liu, X
AU  - Liu X
FAU - Deng, B
AU  - Deng B
FAU - Qian, L
AU  - Qian L
FAU - Liu, X
AU  - Liu X
FAU - Le, Y
AU  - Le Y
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20101130
PL  - Germany
TA  - Diabetologia
JT  - Diabetologia
JID - 0006777
RN  - 0 (Islet Amyloid Polypeptide)
RN  - 0 (Tumor Necrosis Factor-alpha)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - Cells, Cultured
MH  - Electrophoretic Mobility Shift Assay
MH  - Insulin-Secreting Cells/*drug effects/*metabolism
MH  - Islet Amyloid Polypeptide/genetics/*metabolism
MH  - Mice
MH  - Polymerase Chain Reaction
MH  - Tumor Necrosis Factor-alpha/*pharmacology
EDAT- 2010/12/01 06:00
MHDA- 2011/05/26 06:00
CRDT- 2010/12/01 06:00
PHST- 2010/06/30 00:00 [received]
PHST- 2010/10/22 00:00 [accepted]
PHST- 2010/12/01 06:00 [entrez]
PHST- 2010/12/01 06:00 [pubmed]
PHST- 2011/05/26 06:00 [medline]
AID - 10.1007/s00125-010-1972-9 [doi]
PST - ppublish
SO  - Diabetologia. 2011 Mar;54(3):617-26. doi: 10.1007/s00125-010-1972-9. Epub 2010 
      Nov 30.