Diabetologia

, Volume 39, Issue 8, pp 875–890

The harmony of the spheres: inducible nitric oxide synthase and related genes in pancreatic beta cells

  • D. L. Eizirik
  • M. Flodström
  • A. E. Karlsen
  • N. Welsh
Review

DOI: 10.1007/BF00403906

Cite this article as:
Eizirik, D.L., Flodström, M., Karlsen, A.E. et al. Diabetologia (1996) 39: 875. doi:10.1007/BF00403906

Summary

The radical nitric oxide (NO) is a possible mediator of pancreatic beta-cell damage in insulin-dependent diabetes mellitus (IDDM). NO is produced by the enzyme nitric oxide synthase (NOS), in a reaction where arginine is the main substrate. There are different isoforms of NOS, but in the context of immune mediated beta-cell damage the inducible form of NOS (iNOS) is the most relevant. The beta-cell iNOS is similar and encoded by the same gene on chromosome 17 as the iNOS expressed in macrophages and other nucleated cells. iNOS activation depends on gene transcription and de novo enzyme synthesis, and NO seems to induce a negative feedback on iNOS expression. While iNOS mRNA is induced by interleukin-1Β (IL-1Β) alone in rodent insulin-producing cells, a combination of two (IL-1Β + interferon γ) (IFN-γ) or three (IL-1Β + IFNγ + tumour necrosis factor α) cytokines is required for iNOS activation in human pancreatic islets. The promoter region of the murine iNOS gene has at least 25 binding sites for different transcription factors, and the nuclear transcription factor κB is necessary for cytokine-induced iNOS transcription in both rodent and human pancreatic islets. The nature of other transcription factors relevant for iNOS regulation in these cells remains to be determined. Induction of iNOS is paralleled by induction of several other cytokine-dependent genes in beta cells, including argininosuccinate synthetase, cyclooxygenase and manganese superoxide dismutase. Some of these genes may contribute to beta-cell damage, while others are probably involved in beta-cell defence and/or repair. Regulation of iNOS and other related genes in beta cells is complex, and differs in several aspects from that observed in macrophages. There are also important differences in iNOS regulation between rodent and human pancreatic islets. A detailed knowledge of the molecular regulation of these genes in beta cells may be instrumental in the development of new approaches to prevent beta-cell destruction in early IDDM.

Keywords

Nitric oxidenitric oxide synthasepromotertranscription factornuclear factor κBpancreatic isletsbeta cellsinsulin-producing cellsinsulin-dependent diabetes mellitussuperoxide dismutase

Abreviations

iNOS

Inducible nitric oxide synthase

NO

nitric oxide

IDDM

insulin-dependent diabetes mellitus

IL-1Β

interleukm-1Β

IFNγ

interferon γ

TNFα

tumour necrosis factor α

NF-κB

nuclear transcription factor κB

IκB

inhibitor of NF-κB

γ-IRE

interferon γ response element

NOD

non-obese diabetic

BB

bio-breeding

ISRE

IFNα-stimulated response element

HRE

hypoxia-responsive element

IRF

interferon regulatory factor

EMSA

electrophoretic mobility shift assay

PDTC

pyrrolidine dithiocarbamate

LPS

lipopolysac-charides

PKC

protein kinase C

SAPK/JNK

stress activated/c-jun NH2-terminal protein kinases

MAPK

mitogen-activated protein kinase

PAK

p21 (Cdc 42/Rac) activated kinase

MEK

MAPKkinase

CAPK

ceramide-activated protein kinase

JAK

Janus kinases

ATF/CRE

activating transcription factor/cyclic AMP responsive element

DAG

diacylglycerol

PMA

phorbol 12-myristate 13-acetate

AS

argininosuccinate synthetase

iCOX

inducible form of cyclooxygenase

MnSOD

manganese superoxide dismutase

hsp

heat shock protein

IL-1R

interleukin-1 receptor

STAT

signal transducer and activator of transcription

FAD

flavin adenine dinucleotide

FMN

flavin mono-nucleotide

TGF

transforming growth factor

SSRE

shear stress response element

TLCK

tosyl-L-lysine chloromethylketone

GAPDH

glyceraldehyde-3-phosphate dehydro genase

Copyright information

© Springer-Verlag 1996

Authors and Affiliations

  • D. L. Eizirik
    • 1
    • 2
  • M. Flodström
    • 2
  • A. E. Karlsen
    • 3
  • N. Welsh
    • 2
  1. 1.Deparment of Metabolism and EndocrinologyVrije Universiteit BrusselBrusselsBelgium
  2. 2.Department of Medical Cell BiologyUppsala UniversityUppsalaSweden
  3. 3.Steno Diabetes CenterGentofteDenmark