PMID- 12451262
OWN - NLM
STAT- MEDLINE
DCOM- 20021213
LR  - 20220409
IS  - 0041-1337 (Print)
IS  - 0041-1337 (Linking)
VI  - 74
IP  - 9
DP  - 2002 Nov 15
TI  - 17beta-Estradiol protects isolated human pancreatic islets against 
      proinflammatory cytokine-induced cell death: molecular mechanisms and islet 
      functionality.
PG  - 1252-9
AB  - INTRODUCTION: Proinflammatory cytokines (PIC) (interleukin-1beta, 
      interferon-gamma, and tumor necrosis factor alpha) are released after intraportal 
      islet transplantation lead to functional suppression and islet apoptosis. 
      Estradiol has been shown to promote survival of cells undergoing PIC-induced 
      apoptosis. In this study, we evaluated the effects of estradiol on isolated human 
      pancreatic islet (IHPI) survival after exposure to PIC and analyzed potential 
      mechanisms of action. METHODS: Hand-picked, freshly isolated IHPI were incubated 
      with PIC and estradiol. Viability was analyzed from single islet cells stained 
      with ethidium bromide and acridine orange, apoptosis using a quantitative kit, 
      NF-kappaB nuclear translocation using a promoter-Luciferase NF-kappaB responsive 
      construct, mitochondrial permeability transition using the ApoAlert Mitochondrial 
      kit, and caspase 9 by a fluorometric assay. In vitro functionality was examined 
      by static incubation, and a limited number of islets were transplanted in 
      nonobese diabetic, severe combined immunodeficient mice. RESULTS: 
      17beta-Estradiol induced a dose-dependent increase in islet viability, an effect 
      partially reversed by the estrogen receptor antagonist ICI 182,780. In vitro, 
      islets treated with estradiol presented higher stimulation index. Euglycemia was 
      achieved in 6 of 12 animals that received estradiol-treated islets compared with 
      1 of 12 control animals. Lower NF-kappaB nuclear translocation, cytochrome 
      release, and caspase 9 activation occurred in islets treated with estradiol. 
      CONCLUSIONS: Estradiol promoted IHPI survival and improved functionality after 
      PIC exposure in vitro and in vivo after transplantation. The molecular mechanisms 
      involved included a decrease in NF-kappaB nuclear translocation, decrease in 
      mitochondrial cytochrome release, and caspase 9 activation. The use of estradiol 
      might be beneficial in clinical islet transplantation.
FAU - Contreras, Juan L
AU  - Contreras JL
AD  - Transplant Center, University of Alabama at Birmingham, Birmingham, AL, USA. 
      Juan.Contreras@ccc.uab.edu.
FAU - Smyth, Cheryl A
AU  - Smyth CA
FAU - Bilbao, Guadalupe
AU  - Bilbao G
FAU - Young, Carlton J
AU  - Young CJ
FAU - Thompson, J Anthony
AU  - Thompson JA
FAU - Eckhoff, Devin E
AU  - Eckhoff DE
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Transplantation
JT  - Transplantation
JID - 0132144
RN  - 0 (Blood Glucose)
RN  - 0 (Cytokines)
RN  - 0 (Inflammation Mediators)
RN  - 0 (Insulin)
RN  - 0 (NF-kappa B)
RN  - 4TI98Z838E (Estradiol)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Animals
MH  - Biological Transport
MH  - Blood Glucose/analysis
MH  - Cell Death/drug effects
MH  - Cell Nucleus/metabolism
MH  - Cytokines/*pharmacology
MH  - Diabetes Mellitus, Experimental/blood/surgery
MH  - Diabetes Mellitus, Type 2/genetics/surgery
MH  - Estradiol/*pharmacology
MH  - Glucose/pharmacology
MH  - Humans
MH  - In Vitro Techniques
MH  - Inflammation Mediators/*pharmacology
MH  - Insulin/metabolism
MH  - Islets of Langerhans/*drug effects
MH  - Islets of Langerhans Transplantation
MH  - Mice
MH  - Mice, Inbred NOD
MH  - Mice, SCID
MH  - Mitochondria/drug effects/physiology
MH  - NF-kappa B/metabolism
EDAT- 2002/11/27 04:00
MHDA- 2002/12/17 04:00
CRDT- 2002/11/27 04:00
PHST- 2002/11/27 04:00 [pubmed]
PHST- 2002/12/17 04:00 [medline]
PHST- 2002/11/27 04:00 [entrez]
AID - 10.1097/00007890-200211150-00010 [doi]
PST - ppublish
SO  - Transplantation. 2002 Nov 15;74(9):1252-9. doi: 10.1097/00007890-200211150-00010.