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

• Published in: Diabetologia Vol. 47; no. 11; p. 1998
• Main Authors: Karlsen, A E, Heding, P E, Frobøse, H, Rønn, S G, Kruhøffer, M, Orntoft, T F, Darville, M, Eizirik, D L, Pociot, F, Nerup, J, Mandrup-Poulsen, T, Billestrup, N
• Format: Journal Article
• Language: English
• Published: Germany 01.11.2004
• Subjects: Animals; Apoptosis - drug effects; Base Sequence; Cell Line; DNA Primers; Gene Expression Regulation; Interleukin-1 - toxicity; Medicin och hälsovetenskap; NF-kappa B - physiology; Nitric Oxide - metabolism; Oligonucleotide Array Sequence Analysis; Rats; Repressor Proteins - genetics; Repressor Proteins - physiology; Signal Transduction - drug effects; Signal Transduction - physiology; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Transcription Factors - genetics; Transcription Factors - physiology
• ISSN: 0012-186X
• DOI: 10.1007/s00125-004-1568-3

The proinflammatory cytokine IL-1beta induces apoptosis in pancreatic beta cells via pathways dependent on nuclear factor-kappaB (NF-kappaB), 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-1beta- and IFN-gamma-mediated signalling in rat islets and beta cell lines, preventing their deleterious effects. However, the mechanisms underlying SOCS-3 inhibition of IL-1beta signalling and prevention against apoptosis remain unknown. The effect of SOCS-3 expression on the global gene-expression profile following IL-1beta exposure was microarray-analysed using a rat beta cell line (INS-1) with inducible SOCS-3 expression. Subsequently, functional analyses were performed. Eighty-two known genes and several expressed sequence tags (ESTs) changed expression level 2.5-fold or more in response to IL-1beta alone. Following 6 h of IL-1beta 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-1beta 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-1beta-induced NF-kappaB-dependent proapoptotic early response genes were inhibited by SOCS-3 expression, suggesting that SOCS-3 inhibits NF-kappaB-mediated signalling. These observations were experimentally confirmed in functional analyses. This study suggests that there is an unexpected cross-talk between the SOCS/IFN and the IL-1beta 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.