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Article Dans Une Revue Molecular and Cellular Endocrinology Année : 2009

Suppressor of cytokine signalling-3 inhibits tumor necrosis factor-alpha induced apoptosis and signalling in beta cells

Christine Bruun
  • Fonction : Auteur
Peter E. Heding
  • Fonction : Auteur
Sif G. Rønn
  • Fonction : Auteur
Helle Frobøse
  • Fonction : Auteur
Christopher J. Rhodes
  • Fonction : Auteur
Thomas Mandrup-Poulsen
  • Fonction : Auteur
Nils Billestrup
  • Fonction : Auteur correspondant
  • PersonId : 878084

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Résumé

Tumor necrosis factor-alpha (TNFα) is a pro-inflammatory cytokine involved in the pathogenesis of several diseases including type 1 diabetes mellitus (T1DM). TNFα in combination with interleukin-1-beta (IL-1β) and/or interferon-gamma (IFNγ) induce specific destruction of the pancreatic insulin-producing beta cells. Suppressor of cytokine signalling-3 (SOCS-3) proteins regulate signalling induced by a number of cytokines including growth hormone, IFNγ and IL-1β which signals via very distinctive pathways. The objective of this study was to investigate the effect of SOCS-3 on TNFα-induced signalling in beta cells. We found that apoptosis induced by TNFα alone or in combination with IL-1β was suppressed by expression of SOCS-3 in the beta cell line INSr3#2. SOCS-3 inhibited TNFα-induced phosphorylation of the mitogen activated protein kinases ERK1/2, p38 and JNK in INSr3#2 cells and in primary rat islets. Furthermore, SOCS-3 repressed TNFα-induced degradation of IκB, NFκB DNA binding and transcription of the NFκB dependent promoter. Finally, expression of mRNA was induced by TNFα in rat islets in a transient manner with maximum expression after 1-2hours. The ability of SOCS-3 to regulate signalling induced by the three major pro-inflammatory cytokines involved in the pathogenesis of T1DM makes SOCS-3 an interesting therapeutic candidate for protection of the beta cell mass.
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Dates et versions

hal-00514316 , version 1 (02-09-2010)

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Christine Bruun, Peter E. Heding, Sif G. Rønn, Helle Frobøse, Christopher J. Rhodes, et al.. Suppressor of cytokine signalling-3 inhibits tumor necrosis factor-alpha induced apoptosis and signalling in beta cells. Molecular and Cellular Endocrinology, 2009, 311 (1-2), pp.32. ⟨10.1016/j.mce.2009.07.019⟩. ⟨hal-00514316⟩

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