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Diabetologia. 2009 Feb;52(2):281-8. doi: 10.1007/s00125-008-1199-1. Epub 2008 Nov 11.

IL-1beta-induced chemokine and Fas expression are inhibited by suppressor of cytokine signalling-3 in insulin-producing cells.

Author information

1
Steno Diabetes Centre, Niels Steensens Vej 6, NSK2.02, DK-2820 Gentofte, Denmark.

Abstract

AIMS/HYPOTHESIS:

Chemokines recruit activated immune cells to sites of inflammation and are important mediators of insulitis. Activation of the pro-apoptotic receptor Fas leads to apoptosis-mediated death of the Fas-expressing cell. The pro-inflammatory cytokines IL-1beta and IFN-gamma regulate the transcription of genes encoding the Fas receptor and several chemokines. We have previously shown that suppressor of cytokine signalling (SOCS)-3 inhibits IL-1beta- and IFN-gamma-induced nitric oxide production in a beta cell line. The aim of this study was to investigate whether SOCS-3 can influence cytokine-induced Fas and chemokine expression in beta cells.

METHODS:

Using a beta cell line with inducible Socs3 expression or primary neonatal rat islet cells transduced with a Socs3-encoding adenovirus, we employed real-time RT-PCR analysis to investigate whether SOCS-3 affects cytokine-induced chemokine and Fas mRNA expression. The ability of SOCS-3 to influence the activity of cytokine-responsive Fas and Mcp-1 (also known as Ccl2) promoters was measured by reporter analysis.

RESULTS:

IL-1beta induced a time-dependent increase in Mcp-1 and Mip-2 (also known as Cxcl2) mRNA expression after 6 h of stimulation in insulinoma (INS)-1 and neonatal rat islet cells. This induction was inhibited when Socs3 was expressed in the cells. In INS-1 cells, IL-1beta + IFN-gamma induced a tenfold and eightfold increase of Fas mRNA expression after 6 and 24 h, respectively. This induction was inhibited at both time-points when expression of Socs3 was induced. In promoter studies SOCS-3 significantly inhibited the cytokine-induced activity of Mcp-1 and Fas promoter constructs.

CONCLUSIONS/INTERPRETATION:

SOCS-3 inhibits the expression of cytokine-induced chemokine and death-receptor Fas mRNA.

PMID:
19002429
DOI:
10.1007/s00125-008-1199-1
[Indexed for MEDLINE]
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