, Volume 47, Issue 11, pp 1998-2011
Date: 02 Dec 2004

Suppressor of cytokine signalling (SOCS)-3 protects beta cells against IL-1β-mediated toxicity through inhibition of multiple nuclear factor-κB-regulated proapoptotic pathways

Abstract

Aims/hypothesis

The proinflammatory cytokine IL-1β induces apoptosis in pancreatic beta cells via pathways dependent on nuclear factor-κB (NF-κB), mitogen-activated protein kinase, and protein kinase C. We recently showed suppressor of cytokine signalling (SOCS)-3 to be a natural negative feedback regulator of IL-1β- and IFN-γ-mediated signalling in rat islets and beta cell lines, preventing their deleterious effects. However, the mechanisms underlying SOCS-3 inhibition of IL-1β signalling and prevention against apoptosis remain unknown.

Methods

The effect of SOCS-3 expression on the global gene-expression profile following IL-1β exposure was microarray-analysed using a rat beta cell line (INS-1) with inducible SOCS-3 expression. Subsequently, functional analyses were performed.

Results

Eighty-two known genes and several expressed sequence tags (ESTs) changed expression level 2.5-fold or more in response to IL-1β alone. Following 6 h of IL-1β exposure, 23 transcripts were up-regulated. Of these, several, including all eight transcripts relating to immune/inflammatory response pathways, were suppressed by SOCS-3. Following 24 h of IL-1β exposure, secondary response genes were detected, affecting metabolism, energy generation, protein synthesis and degradation, growth arrest, and apoptosis. The majority of these changes were prevented by SOCS-3 expression. Multiple IL-1β-induced NF-κB-dependent proapoptotic early response genes were inhibited by SOCS-3 expression, suggesting that SOCS-3 inhibits NF-κB-mediated signalling. These observations were experimentally confirmed in functional analyses.

Conclusions/interpretation

This study suggests that there is an unexpected cross-talk between the SOCS/IFN and the IL-1β pathways of signalling in pancreatic beta cells, which could lead to a novel perspective of blocking two important proapoptotic pathways in pancreatic beta cells by influencing a single signalling molecule, namely SOCS-3.

A.E. Karlsen and P.E. Heding shared first authorship