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

Christine Bruun; Peter E Heding; Sif G Rønn; Helle Frobøse; Christopher J Rhodes; Thomas Mandrup-Poulsen; Nils Billestrup

doi:10.1016/j.mce.2009.07.019

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

Christine Bruun, Peter E Heding, Sif G Rønn, Helle Frobøse, Christopher J Rhodes, Thomas Mandrup-Poulsen, Nils Billestrup

28 Citations (Scopus)

Abstract

Tumor necrosis factor-alpha (TNFalpha) is a pro-inflammatory cytokine involved in the pathogenesis of several diseases including type 1 diabetes mellitus (T1DM). TNFalpha in combination with interleukin-1-beta (IL-1beta) and/or interferon-gamma (IFNgamma) induces 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, IFNgamma and IL-1beta which signals via very distinctive pathways. The objective of this study was to investigate the effect of SOCS-3 on TNFalpha-induced signalling in beta cells. We found that apoptosis induced by TNFalpha alone or in combination with IL-1beta was suppressed by expression of SOCS-3 in the beta cell line INSr3#2. SOCS-3 inhibited TNFalpha-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 TNFalpha-induced degradation of IkappaB, NFkappaB DNA binding and transcription of the NFkappaB-dependent MnSOD promoter. Finally, expression of Socs-3 mRNA was induced by TNFalpha in rat islets in a transient manner with maximum expression after 1-2h. 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.

Original language	English
Journal	Molecular and Cellular Endocrinology
Volume	311
Issue number	1-2
Pages (from-to)	32-8
Number of pages	6
ISSN	0303-7207
DOIs	https://doi.org/10.1016/j.mce.2009.07.019
Publication status	Published - 2009

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@article{12ef68c0333411df8ed1000ea68e967b,

title = "Suppressor of cytokine signalling-3 inhibits Tumor necrosis factor-alpha induced apoptosis and signalling in beta cells",

abstract = "Tumor necrosis factor-alpha (TNFalpha) is a pro-inflammatory cytokine involved in the pathogenesis of several diseases including type 1 diabetes mellitus (T1DM). TNFalpha in combination with interleukin-1-beta (IL-1beta) and/or interferon-gamma (IFNgamma) induces 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, IFNgamma and IL-1beta which signals via very distinctive pathways. The objective of this study was to investigate the effect of SOCS-3 on TNFalpha-induced signalling in beta cells. We found that apoptosis induced by TNFalpha alone or in combination with IL-1beta was suppressed by expression of SOCS-3 in the beta cell line INSr3#2. SOCS-3 inhibited TNFalpha-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 TNFalpha-induced degradation of IkappaB, NFkappaB DNA binding and transcription of the NFkappaB-dependent MnSOD promoter. Finally, expression of Socs-3 mRNA was induced by TNFalpha in rat islets in a transient manner with maximum expression after 1-2h. 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.",

author = "Christine Bruun and Heding, {Peter E} and R{\o}nn, {Sif G} and Helle Frob{\o}se and Rhodes, {Christopher J} and Thomas Mandrup-Poulsen and Nils Billestrup",

note = "Keywords: Animals; Apoptosis; DNA; Enzyme Activation; Female; Gene Expression Regulation; Humans; I-kappa B Proteins; Insulin-Secreting Cells; Interleukin-1beta; Mice; Middle Aged; Mitogen-Activated Protein Kinases; NF-kappa B; Phosphorylation; Promoter Regions, Genetic; Protein Binding; Protein Processing, Post-Translational; Rats; Signal Transduction; Superoxide Dismutase; Suppressor of Cytokine Signaling Proteins; Tumor Necrosis Factor-alpha Times Cited: 0ArticleEnglishBillestrup, NHagedorn Res Inst, Niels Steensens Vej 6,NSK2-02, DK-2820 Gentofte, DenmarkCited References Count: 35502VTELSEVIER IRELAND LTDELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELANDCLARE",

year = "2009",

doi = "10.1016/j.mce.2009.07.019",

language = "English",

volume = "311",

pages = "32--8",

journal = "Molecular and Cellular Endocrinology",

issn = "0303-7207",

publisher = "Elsevier Ireland Ltd",

number = "1-2",

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TY - JOUR

T1 - Suppressor of cytokine signalling-3 inhibits Tumor necrosis factor-alpha induced apoptosis and signalling in beta cells

AU - Bruun, Christine

AU - Heding, Peter E

AU - Rønn, Sif G

AU - Frobøse, Helle

AU - Rhodes, Christopher J

AU - Mandrup-Poulsen, Thomas

AU - Billestrup, Nils

N1 - Keywords: Animals; Apoptosis; DNA; Enzyme Activation; Female; Gene Expression Regulation; Humans; I-kappa B Proteins; Insulin-Secreting Cells; Interleukin-1beta; Mice; Middle Aged; Mitogen-Activated Protein Kinases; NF-kappa B; Phosphorylation; Promoter Regions, Genetic; Protein Binding; Protein Processing, Post-Translational; Rats; Signal Transduction; Superoxide Dismutase; Suppressor of Cytokine Signaling Proteins; Tumor Necrosis Factor-alpha Times Cited: 0ArticleEnglishBillestrup, NHagedorn Res Inst, Niels Steensens Vej 6,NSK2-02, DK-2820 Gentofte, DenmarkCited References Count: 35502VTELSEVIER IRELAND LTDELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELANDCLARE

PY - 2009

Y1 - 2009

N2 - Tumor necrosis factor-alpha (TNFalpha) is a pro-inflammatory cytokine involved in the pathogenesis of several diseases including type 1 diabetes mellitus (T1DM). TNFalpha in combination with interleukin-1-beta (IL-1beta) and/or interferon-gamma (IFNgamma) induces 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, IFNgamma and IL-1beta which signals via very distinctive pathways. The objective of this study was to investigate the effect of SOCS-3 on TNFalpha-induced signalling in beta cells. We found that apoptosis induced by TNFalpha alone or in combination with IL-1beta was suppressed by expression of SOCS-3 in the beta cell line INSr3#2. SOCS-3 inhibited TNFalpha-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 TNFalpha-induced degradation of IkappaB, NFkappaB DNA binding and transcription of the NFkappaB-dependent MnSOD promoter. Finally, expression of Socs-3 mRNA was induced by TNFalpha in rat islets in a transient manner with maximum expression after 1-2h. 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.

AB - Tumor necrosis factor-alpha (TNFalpha) is a pro-inflammatory cytokine involved in the pathogenesis of several diseases including type 1 diabetes mellitus (T1DM). TNFalpha in combination with interleukin-1-beta (IL-1beta) and/or interferon-gamma (IFNgamma) induces 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, IFNgamma and IL-1beta which signals via very distinctive pathways. The objective of this study was to investigate the effect of SOCS-3 on TNFalpha-induced signalling in beta cells. We found that apoptosis induced by TNFalpha alone or in combination with IL-1beta was suppressed by expression of SOCS-3 in the beta cell line INSr3#2. SOCS-3 inhibited TNFalpha-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 TNFalpha-induced degradation of IkappaB, NFkappaB DNA binding and transcription of the NFkappaB-dependent MnSOD promoter. Finally, expression of Socs-3 mRNA was induced by TNFalpha in rat islets in a transient manner with maximum expression after 1-2h. 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.

U2 - 10.1016/j.mce.2009.07.019

DO - 10.1016/j.mce.2009.07.019

M3 - Journal article

C2 - 19643162

SN - 0303-7207

VL - 311

SP - 32

EP - 38

JO - Molecular and Cellular Endocrinology

JF - Molecular and Cellular Endocrinology

IS - 1-2

ER -

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

Abstract

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