Cytokines Interleukin-1β and Tumor Necrosis Factor-α Regulate Different Transcriptional and Alternative Splicing Networks in Primary β-Cells

Ortis, Fernanda; Naamane, Najib; Flamez, Daisy; Ladrière, Laurence; Moore, Fabrice; Cunha, Daniel Andrade Da; Colli, Máikel Luís; Thykjær, Thomas; Thorsen, Kasper; Ørntoft, Torben F.; Eizirik, Décio L.

doi:10.2337/db09-1159

Cited by 141 publications

(160 citation statements)

References 49 publications

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“…7g, h). We have previously shown that IRF-7 plays an important role in the regulation of chemokine expression by TNF-α+IFN-γ [42], but this does not explain the present observations, as STAT1 KD decreased IRF-7 expression (ESM Fig. 4b).…”

Section: Il-17a Exacerbates Cytokine-induced Apoptosis In Rat Ins-1e contrasting

confidence: 90%

“…The chemokine 'signature' of pancreatic islets seems to vary depending on the cytokine stimulus provided. For instance, the pattern of chemokines induced by IL-1β+IFN-γ in pancreatic beta cells is markedly different from that induced by TNF-α+IFN-γ [42]. We showed here that IL-17A alone induces a mild increase in expression of CXCL1, CXCL8, CCL2 and CCL20, in addition to its stimulatory effect on human islets exposed to IL-1β+IFN-γ and TNF-α+IFN-γ.…”

Section: Discussionmentioning

confidence: 61%

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IL-17A increases the expression of proinflammatory chemokines in human pancreatic islets

et al. 2013

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Aims/hypothesis Cytotoxic T cells and macrophages contribute to beta cell destruction in type 1 diabetes at least in part through the production of cytokines such as IL-1β, IFN-γ and TNF-α. We have recently shown the IL-17 pathway to be activated in circulating T cells and pancreatic islets of type 1 diabetes patients. Here, we studied whether IL-17A upregulates the production of chemokines by human pancreatic islets, thus contributing to the build-up of insulitis. Methods Human islets (from 18 donors), INS-1E cells and islets from wild-type and Stat1 knockout mice were studied. Dispersed islet cells were left untreated, or were treated with IL-17A alone or together with IL-1β+IFN-γ or TNF-α+IFN-γ.RNA interference was used to knock down signal transducer and activator of transcription 1 (STAT1). Chemokine expression was assessed by quantitative RT-PCR, ELISA and histology. Cell viability was evaluated with nuclear dyes. Results IL-17A augmented IL-1β+IFN-γ-and TNF-α+IFN-γ-induced chemokine mRNA and protein expression, and apoptosis in human islets. Beta cells were at least in part the source of chemokine production. Knockdown of STAT1 in human islets prevented cytokine-or IL-17A+cytokine-induced apoptosis and the expression of particular chemokines, e.g. chemokine (C-X-C motif) ligands 9 and 10. Similar observations were made in islets isolated from Stat1 knockout mice. Conclusions/interpretation Our findings indicate that IL-17A exacerbates proinflammatory chemokine expression and secretion by human islets exposed to cytokines. This suggests that IL-17A contributes to the pathogenesis of type 1 diabetes by two mechanisms, namely the exacerbation of beta cell apoptosis and increased local production of chemokines, thus potentially aggravating insulitis.

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Section: Il-17a Exacerbates Cytokine-induced Apoptosis In Rat Ins-1e contrasting

confidence: 90%

Section: Discussionmentioning

confidence: 61%

IL-17A increases the expression of proinflammatory chemokines in human pancreatic islets

et al. 2013

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“…In order to obtain a broader evaluation of the impact of cytokine exposure on primary human or rodent islet cells, we made a global comparison of cytokine-modulated gene expression in human and mouse islets, and in FACS-purified rat beta cells based on previously published microarray and RNA sequencing data [17,[42][43][44][45]. There was an overall higher ranking similarity between human and mouse gene expression than between human and rat gene expression for both up-and downregulated genes (ESM Fig.…”

Section: Resultsmentioning

confidence: 99%

Cytokines induce endoplasmic reticulum stress in human, rat and mouse beta cells via different mechanisms

et al. 2015

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Aims/hypothesis Proinflammatory cytokines contribute to beta cell damage in type 1 diabetes in part through activation of endoplasmic reticulum (ER) stress. In rat beta cells, cytokineinduced ER stress involves NO production and consequent inhibition of the ER Ca 2+ transporting ATPase sarco/ endoplasmic reticulum Ca 2+ pump 2 (SERCA2B). However, the mechanisms by which cytokines induce ER stress and apoptosis in mouse and human pancreatic beta cells remain unclear. The purpose of this study is to elucidate the role of ER stress on cytokine-induced beta cell apoptosis in these three species and thus solve ongoing controversies in the field. Methods Rat and mouse insulin-producing cells, human pancreatic islets and human EndoC-βH1 cells were exposed to the cytokines IL-1β, TNF-α and IFN-γ, with or without NO inhibition. A global comparison of cytokine-modulated gene expression in human, mouse and rat beta cells was also performed. The chemical chaperone tauroursodeoxycholic acid (TUDCA) and suppression of C/EBP homologous protein (CHOP) were used to assess the role of ER stress in cytokineinduced apoptosis of human beta cells. Results NO plays a key role in cytokine-induced ER stress in rat islets, but not in mouse or human islets. Bioinformatics analysis indicated greater similarity between human and mouse than between human and rat global gene expression after cytokine exposure. The chemical chaperone TUDCA and suppression of CHOP or c-Jun N-terminal kinase (JNK) protected human beta cells against cytokine-induced apoptosis. Conclusions/interpretation These observations clarify previous results that were discrepant owing to the use of islets from different species, and confirm that cytokine-induced ER stress contributes to human beta cell death, at least in part via JNK activation.

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“…This was previously shown to be mediated by TNF-a-induced IRF-7 expression. 44 As CHOP modulates IRF-7 expression, the observed effects of CHOP KD on the expression of these chemokines probably occur through the combined decreased activity of NF-kB and IRF-7. These data strongly suggest that CHOP contributes to inflammation.…”

Section: Discussionmentioning

confidence: 99%

C/EBP homologous protein contributes to cytokine-induced pro-inflammatory responses and apoptosis in β-cells

et al. 2012

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Induction of the C/EBP homologous protein (CHOP) is considered a key event for endoplasmic reticulum (ER) stress-mediated apoptosis. Type 1 diabetes (T1D) is characterized by an autoimmune destruction of the pancreatic b-cells. Pro-inflammatory cytokines are early mediators of b-cell death in T1D. Cytokines induce ER stress and CHOP overexpression in b-cells, but the role for CHOP overexpression in cytokine-induced b-cell apoptosis remains controversial. We presently observed that CHOP knockdown (KD) prevents cytokine-mediated degradation of the anti-apoptotic proteins B-cell lymphoma 2 (Bcl-2) and myeloid cell leukemia sequence 1 (Mcl-1), thereby decreasing the cleavage of executioner caspases 9 and 3, and apoptosis. Nuclear factor-jB (NF-jB) is a crucial transcription factor regulating b-cell apoptosis and inflammation. CHOP KD resulted in reduced cytokine-induced NF-jB activity and expression of key NF-jB target genes involved in apoptosis and inflammation, including iNOS, FAS, IRF-7, IL-15, CCL5 and CXCL10. This was due to decreased IjB degradation and p65 translocation to the nucleus. The present data suggest that CHOP has a dual role in promoting b-cell death: (1) CHOP directly contributes to cytokine-induced b-cell apoptosis by promoting cytokine-induced mitochondrial pathways of apoptosis; and (2) by supporting the NF-jB activation and subsequent cytokine/chemokine expression, CHOP may contribute to apoptosis and the chemo attraction of mononuclear cells to the islets during insulitis. Type 1 diabetes (T1D) is a severe chronic disease resulting from an autoimmune destruction of the pancreatic b-cells. The incidence of T1D has been rising steadily in developed countries from the 1950s to the present day, with the recent, alarming prediction that it will double in children under the age of 5 years by 2020. 1 b-cell loss in T1DM occurs slowly over years and 480% of the b-cell mass is usually lost at the time of diagnosis. Because of the excessive mortality associated with complications of T1D and the increasing incidence of childhood diabetes, 2 there is an ongoing effort to develop novel strategies for a better treatment and hopefully, prevention of T1D.In T1D, b-cells cooperate with the immune system to its own destruction by activating pro-apoptotic pathways and secreting chemokines/cytokines that contribute to islet inflammation. 3 These responses are mostly triggered via the secretion of the pro-inflammatory cytokines interleukin-1b (IL-1b), tumor necrosis factor-a (TNF-a) and interferon-g (IFN-g) by the infiltrated immune cells. The mechanisms regulating cytokine-mediated b-cell apoptosis and pro-inflammatory responses are intricate and include, but are not restricted to, the activation of the transcription factors nuclear factor-kB (NF-kB) and STAT-1, the c-Jun N-terminal kinases (JNK), endoplasmic reticulum (ER) stress pathways and the intrinsic mitochondrial apoptotic pathways. [3][4][5][6][7] NF-kB activation is due to cytokine-dependent activation of the inhibitor of k-light polypeptide gene enha...

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Cytokines Interleukin-1β and Tumor Necrosis Factor-α Regulate Different Transcriptional and Alternative Splicing Networks in Primary β-Cells

Cited by 141 publications

References 49 publications

IL-17A increases the expression of proinflammatory chemokines in human pancreatic islets

IL-17A increases the expression of proinflammatory chemokines in human pancreatic islets

Cytokines induce endoplasmic reticulum stress in human, rat and mouse beta cells via different mechanisms

C/EBP homologous protein contributes to cytokine-induced pro-inflammatory responses and apoptosis in β-cells

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