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

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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.

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Abbreviations

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

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Authors and Affiliations

  1. Deparment of Metabolism and Endocrinology, Vrije Universiteit Brussel, Laarbee-klan 103, B-1090, Brussels, Belgium

    D. L. Eizirik

  2. Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden

    D. L. Eizirik, M. Flodström & N. Welsh

  3. Steno Diabetes Center, Gentofte, Denmark

    A. E. Karlsen

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  1. D. L. Eizirik
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  2. M. Flodström
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  3. A. E. Karlsen
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  4. N. Welsh
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Eizirik, D.L., Flodström, M., Karlsen, A.E. et al. The harmony of the spheres: inducible nitric oxide synthase and related genes in pancreatic beta cells. Diabetologia 39, 875–890 (1996). https://doi.org/10.1007/BF00403906

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