CD154 Induces Interleukin-6 Secretion by Kidney Tubular Epithelial Cells under Hypoxic Conditions: Inhibition by Chloroquine
Identifieur interne : 000694 ( Pmc/Curation ); précédent : 000693; suivant : 000695CD154 Induces Interleukin-6 Secretion by Kidney Tubular Epithelial Cells under Hypoxic Conditions: Inhibition by Chloroquine
Auteurs : Antoine Dewitte [France] ; Julien Villeneuve [Royaume-Uni] ; Sébastien Lepreux [France] ; Marion Bouchecareilh [France] ; Xavier Gauthereau [France] ; Claire Rigothier [France] ; Christian Combe [France] ; Alexandre Ouattara [France] ; Jean Ripoche [France]Source :
- Mediators of Inflammation [ 0962-9351 ] ; 2020.
Abstract
Inflammation is a major contributor to tubular epithelium injury in kidney disorders, and the involvement of blood platelets in driving inflammation is increasingly stressed. CD154, the ligand of CD40, is one of the mediators supporting platelet proinflammatory properties. Although hypoxia is an essential constituent of the inflammatory reaction, if and how platelets and CD154 regulate inflammation in hypoxic conditions remain unclear. Here, we studied the control by CD154 of the proinflammatory cytokine interleukin- (IL-) 6 secretion in short-term oxygen (O2) deprivation conditions, using the HK-2 cell line as a kidney tubular epithelial cell (TEC) model. IL-6 secretion was markedly stimulated by CD154 after 1 to 3 hours of hypoxic stress. Both intracellular IL-6 expression and secretion were stimulated by CD154 and associated with a strong upregulation of IL-6 mRNA and increased transcription. Searching for inhibitors of CD154-mediated IL-6 production by HK-2 cells in hypoxic conditions, we observed that chloroquine, a drug that has been repurposed as an anti-inflammatory agent, alleviated this induction. Therefore, CD154 is a potent early stimulus for IL-6 secretion by TECs in O2 deprivation conditions, a mechanism likely to take part in the deleterious inflammatory consequences of platelet activation in kidney tubular injury. The inhibition of CD154-induced IL-6 production by chloroquine suggests the potential usefulness of this drug as a therapeutic adjunct in conditions associated with acute kidney injury.
Url:
DOI: 10.1155/2020/6357046
PubMed: 32089648
PubMed Central: 7013356
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Bordeaux</wicri:regionArea></affiliation></author><author><name sortKey="Ouattara, Alexandre" sort="Ouattara, Alexandre" uniqKey="Ouattara A" first="Alexandre" last="Ouattara">Alexandre Ouattara</name><affiliation wicri:level="1"><nlm:aff id="I1">Department of Anesthesia and Critical Care, CHU de Bordeaux, F-33600 Pessac, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Department of Anesthesia and Critical Care, CHU de Bordeaux, F-33600 Pessac</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="I8">INSERM, UMR1034 Biology of Cardiovascular Diseases, Université de Bordeaux, F-33600 Pessac, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>INSERM, UMR1034 Biology of Cardiovascular Diseases, Université de Bordeaux, F-33600 Pessac</wicri:regionArea></affiliation></author><author><name sortKey="Ripoche, Jean" sort="Ripoche, Jean" uniqKey="Ripoche J" first="Jean" last="Ripoche">Jean Ripoche</name><affiliation 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level="a" type="main">CD154 Induces Interleukin-6 Secretion by Kidney Tubular Epithelial Cells under Hypoxic Conditions: Inhibition by Chloroquine</title><author><name sortKey="Dewitte, Antoine" sort="Dewitte, Antoine" uniqKey="Dewitte A" first="Antoine" last="Dewitte">Antoine Dewitte</name><affiliation wicri:level="1"><nlm:aff id="I1">Department of Anesthesia and Critical Care, CHU de Bordeaux, F-33600 Pessac, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Department of Anesthesia and Critical Care, CHU de Bordeaux, F-33600 Pessac</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="I2">INSERM, UMR1026 Bioingénierie Tissulaire (Biotis), Université de Bordeaux, F-33000 Bordeaux, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>INSERM, UMR1026 Bioingénierie Tissulaire (Biotis), Université de Bordeaux, F-33000 Bordeaux</wicri:regionArea></affiliation></author><author><name sortKey="Villeneuve, Julien" sort="Villeneuve, Julien" uniqKey="Villeneuve J" first="Julien" last="Villeneuve">Julien Villeneuve</name><affiliation wicri:level="1"><nlm:aff id="I3">Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, The Keith Peters Building, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, The Keith Peters Building, Cambridge Biomedical Campus, Cambridge CB2 0XY</wicri:regionArea></affiliation></author><author><name sortKey="Lepreux, Sebastien" sort="Lepreux, Sebastien" uniqKey="Lepreux S" first="Sébastien" last="Lepreux">Sébastien Lepreux</name><affiliation wicri:level="1"><nlm:aff id="I2">INSERM, UMR1026 Bioingénierie Tissulaire (Biotis), Université de Bordeaux, F-33000 Bordeaux, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>INSERM, UMR1026 Bioingénierie Tissulaire (Biotis), Université de Bordeaux, F-33000 Bordeaux</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="I4">Pathology Unit, CH de Libourne, F-33505 Libourne, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Pathology Unit, CH de Libourne, F-33505 Libourne</wicri:regionArea></affiliation></author><author><name sortKey="Bouchecareilh, Marion" sort="Bouchecareilh, Marion" uniqKey="Bouchecareilh M" first="Marion" last="Bouchecareilh">Marion Bouchecareilh</name><affiliation wicri:level="1"><nlm:aff id="I5">INSERM, UMR1053 Bordeaux Research in Translational Oncology (BaRITOn), Université de Bordeaux, F-33000 Bordeaux, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>INSERM, UMR1053 Bordeaux Research in Translational Oncology (BaRITOn), Université de Bordeaux, F-33000 Bordeaux</wicri:regionArea></affiliation></author><author><name sortKey="Gauthereau, Xavier" sort="Gauthereau, Xavier" uniqKey="Gauthereau X" first="Xavier" last="Gauthereau">Xavier Gauthereau</name><affiliation wicri:level="1"><nlm:aff id="I6">CNRS, UMR5164, Université de Bordeaux, F-33000 Bordeaux, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>CNRS, UMR5164, Université de Bordeaux, F-33000 Bordeaux</wicri:regionArea></affiliation></author><author><name sortKey="Rigothier, Claire" sort="Rigothier, Claire" uniqKey="Rigothier C" first="Claire" last="Rigothier">Claire Rigothier</name><affiliation wicri:level="1"><nlm:aff id="I2">INSERM, UMR1026 Bioingénierie Tissulaire (Biotis), Université de Bordeaux, F-33000 Bordeaux, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>INSERM, UMR1026 Bioingénierie Tissulaire (Biotis), Université de Bordeaux, F-33000 Bordeaux</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="I7">Department of Nephrology-Transplantation-Dialysis, CHU de Bordeaux, F-33076 Bordeaux, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Department of Nephrology-Transplantation-Dialysis, CHU de Bordeaux, F-33076 Bordeaux</wicri:regionArea></affiliation></author><author><name sortKey="Combe, Christian" sort="Combe, Christian" uniqKey="Combe C" first="Christian" last="Combe">Christian Combe</name><affiliation wicri:level="1"><nlm:aff id="I2">INSERM, UMR1026 Bioingénierie Tissulaire (Biotis), Université de Bordeaux, F-33000 Bordeaux, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>INSERM, UMR1026 Bioingénierie Tissulaire (Biotis), Université de Bordeaux, F-33000 Bordeaux</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="I7">Department of Nephrology-Transplantation-Dialysis, CHU de Bordeaux, F-33076 Bordeaux, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Department of Nephrology-Transplantation-Dialysis, CHU de Bordeaux, F-33076 Bordeaux</wicri:regionArea></affiliation></author><author><name sortKey="Ouattara, Alexandre" sort="Ouattara, Alexandre" uniqKey="Ouattara A" first="Alexandre" last="Ouattara">Alexandre Ouattara</name><affiliation wicri:level="1"><nlm:aff id="I1">Department of Anesthesia and Critical Care, CHU de Bordeaux, F-33600 Pessac, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Department of Anesthesia and Critical Care, CHU de Bordeaux, F-33600 Pessac</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="I8">INSERM, UMR1034 Biology of Cardiovascular Diseases, Université de Bordeaux, F-33600 Pessac, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>INSERM, UMR1034 Biology of Cardiovascular Diseases, Université de Bordeaux, F-33600 Pessac</wicri:regionArea></affiliation></author><author><name sortKey="Ripoche, Jean" sort="Ripoche, Jean" uniqKey="Ripoche J" first="Jean" last="Ripoche">Jean Ripoche</name><affiliation wicri:level="1"><nlm:aff id="I2">INSERM, UMR1026 Bioingénierie Tissulaire (Biotis), Université de Bordeaux, F-33000 Bordeaux, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>INSERM, UMR1026 Bioingénierie Tissulaire (Biotis), Université de Bordeaux, F-33000 Bordeaux</wicri:regionArea></affiliation></author></analytic><series><title level="j">Mediators of Inflammation</title><idno type="ISSN">0962-9351</idno><idno type="eISSN">1466-1861</idno><imprint><date when="2020">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Inflammation is a major contributor to tubular epithelium injury in kidney disorders, and the involvement of blood platelets in driving inflammation is increasingly stressed. CD154, the ligand of CD40, is one of the mediators supporting platelet proinflammatory properties. Although hypoxia is an essential constituent of the inflammatory reaction, if and how platelets and CD154 regulate inflammation in hypoxic conditions remain unclear. Here, we studied the control by CD154 of the proinflammatory cytokine interleukin- (IL-) 6 secretion in short-term oxygen (O<sub>2</sub>) deprivation conditions, using the HK-2 cell line as a kidney tubular epithelial cell (TEC) model. IL-6 secretion was markedly stimulated by CD154 after 1 to 3 hours of hypoxic stress. Both intracellular IL-6 expression and secretion were stimulated by CD154 and associated with a strong upregulation of IL-6 mRNA and increased transcription. Searching for inhibitors of CD154-mediated IL-6 production by HK-2 cells in hypoxic conditions, we observed that chloroquine, a drug that has been repurposed as an anti-inflammatory agent, alleviated this induction. Therefore, CD154 is a potent early stimulus for IL-6 secretion by TECs in O<sub>2</sub> deprivation conditions, a mechanism likely to take part in the deleterious inflammatory consequences of platelet activation in kidney tubular injury. The inhibition of CD154-induced IL-6 production by chloroquine suggests the potential usefulness of this drug as a therapeutic adjunct in conditions associated with acute kidney injury.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Taylor, C T" uniqKey="Taylor C">C. T. Taylor</name></author><author><name sortKey="Doherty, G" uniqKey="Doherty G">G. Doherty</name></author><author><name sortKey="Fallon, P G" uniqKey="Fallon P">P. G. Fallon</name></author><author><name sortKey="Cummins, E P" uniqKey="Cummins E">E. P. Cummins</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Eltzschig, H K" uniqKey="Eltzschig H">H. K. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Mediators Inflamm</journal-id><journal-id journal-id-type="iso-abbrev">Mediators Inflamm</journal-id><journal-id journal-id-type="publisher-id">MI</journal-id><journal-title-group><journal-title>Mediators of Inflammation</journal-title></journal-title-group><issn pub-type="ppub">0962-9351</issn><issn pub-type="epub">1466-1861</issn><publisher><publisher-name>Hindawi</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">32089648</article-id><article-id pub-id-type="pmc">7013356</article-id><article-id pub-id-type="doi">10.1155/2020/6357046</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group></article-categories><title-group><article-title>CD154 Induces Interleukin-6 Secretion by Kidney Tubular Epithelial Cells under Hypoxic Conditions: Inhibition by Chloroquine</article-title></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0003-1112-4845</contrib-id><name><surname>Dewitte</surname><given-names>Antoine</given-names></name><email>antoine.dewitte@chu-bordeaux.fr</email><xref ref-type="aff" rid="I1"><sup>1</sup></xref><xref ref-type="aff" rid="I2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-5430-1680</contrib-id><name><surname>Villeneuve</surname><given-names>Julien</given-names></name><xref ref-type="aff" rid="I3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lepreux</surname><given-names>Sébastien</given-names></name><xref ref-type="aff" rid="I2"><sup>2</sup></xref><xref ref-type="aff" rid="I4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Bouchecareilh</surname><given-names>Marion</given-names></name><xref ref-type="aff" rid="I5"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Gauthereau</surname><given-names>Xavier</given-names></name><xref ref-type="aff" rid="I6"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Rigothier</surname><given-names>Claire</given-names></name><xref ref-type="aff" rid="I2"><sup>2</sup></xref><xref ref-type="aff" rid="I7"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>Combe</surname><given-names>Christian</given-names></name><xref ref-type="aff" rid="I2"><sup>2</sup></xref><xref ref-type="aff" rid="I7"><sup>7</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-7346-7539</contrib-id><name><surname>Ouattara</surname><given-names>Alexandre</given-names></name><xref ref-type="aff" rid="I1"><sup>1</sup></xref><xref ref-type="aff" rid="I8"><sup>8</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ripoche</surname><given-names>Jean</given-names></name><xref ref-type="aff" rid="I2"><sup>2</sup></xref></contrib></contrib-group><aff id="I1"><sup>1</sup>Department of Anesthesia and Critical Care, CHU de Bordeaux, F-33600 Pessac, France</aff><aff id="I2"><sup>2</sup>INSERM, UMR1026 Bioingénierie Tissulaire (Biotis), Université de Bordeaux, F-33000 Bordeaux, France</aff><aff id="I3"><sup>3</sup>Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, The Keith Peters Building, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK</aff><aff id="I4"><sup>4</sup>Pathology Unit, CH de Libourne, F-33505 Libourne, France</aff><aff id="I5"><sup>5</sup>INSERM, UMR1053 Bordeaux Research in Translational Oncology (BaRITOn), Université de Bordeaux, F-33000 Bordeaux, France</aff><aff id="I6"><sup>6</sup>CNRS, UMR5164, Université de Bordeaux, F-33000 Bordeaux, France</aff><aff id="I7"><sup>7</sup>Department of Nephrology-Transplantation-Dialysis, CHU de Bordeaux, F-33076 Bordeaux, France</aff><aff id="I8"><sup>8</sup>INSERM, UMR1034 Biology of Cardiovascular Diseases, Université de Bordeaux, F-33600 Pessac, France</aff><author-notes><fn fn-type="other"><p>Academic Editor: Michele T. Pritchard</p></fn></author-notes><pub-date pub-type="collection"><year>2020</year></pub-date><pub-date pub-type="epub"><day>31</day><month>1</month><year>2020</year></pub-date><volume>2020</volume><elocation-id>6357046</elocation-id><history><date date-type="received"><day>21</day><month>7</month><year>2019</year></date><date date-type="rev-recd"><day>22</day><month>11</month><year>2019</year></date><date date-type="accepted"><day>7</day><month>1</month><year>2020</year></date></history><permissions><copyright-statement>Copyright © 2020 Antoine Dewitte et al.</copyright-statement><copyright-year>2020</copyright-year><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p></license></permissions><abstract><p>Inflammation is a major contributor to tubular epithelium injury in kidney disorders, and the involvement of blood platelets in driving inflammation is increasingly stressed. CD154, the ligand of CD40, is one of the mediators supporting platelet proinflammatory properties. Although hypoxia is an essential constituent of the inflammatory reaction, if and how platelets and CD154 regulate inflammation in hypoxic conditions remain unclear. Here, we studied the control by CD154 of the proinflammatory cytokine interleukin- (IL-) 6 secretion in short-term oxygen (O<sub>2</sub>) deprivation conditions, using the HK-2 cell line as a kidney tubular epithelial cell (TEC) model. IL-6 secretion was markedly stimulated by CD154 after 1 to 3 hours of hypoxic stress. Both intracellular IL-6 expression and secretion were stimulated by CD154 and associated with a strong upregulation of IL-6 mRNA and increased transcription. Searching for inhibitors of CD154-mediated IL-6 production by HK-2 cells in hypoxic conditions, we observed that chloroquine, a drug that has been repurposed as an anti-inflammatory agent, alleviated this induction. Therefore, CD154 is a potent early stimulus for IL-6 secretion by TECs in O<sub>2</sub> deprivation conditions, a mechanism likely to take part in the deleterious inflammatory consequences of platelet activation in kidney tubular injury. The inhibition of CD154-induced IL-6 production by chloroquine suggests the potential usefulness of this drug as a therapeutic adjunct in conditions associated with acute kidney injury.</p></abstract><funding-group><award-group><funding-source>MSDAvenir</funding-source></award-group><award-group><funding-source>Horizon 2020 Framework Programme</funding-source><award-id>842919</award-id></award-group></funding-group></article-meta></front><floats-group><fig id="fig1" orientation="portrait" position="float"><label>Figure 1</label><caption><p>CD40 expression by HK-2 cells. (a, b) CD40 expression by HK-2 cells was analyzed by flow cytometry to assess the surface expression of CD40 (a) and immunofluorescence microscopy to assess the total expression (surface and intracellular pool) (b; nuclei are counterstained with DAPI). (c, d) HK-2 cells were treated with IL-1<italic>α</italic> (200 IU/mL), TNF-<italic>α</italic> (200 IU/mL), or interferon-<italic>γ</italic> (200 IU/mL) for 24 hours and CD40 mRNA expression analyzed by RT-qPCR (c) (<italic>n</italic> = 4, <sup>∗</sup>significant relatively to control), or by flow cytometry (d) (<italic>n</italic> = 3, <sup>∗</sup>significant relatively to control). (e) Treatment of HK-2 cells with rsCD154 activates ERK and JNK pathways. HK-2 cells were incubated with rsCD154 and cells lysed at indicated time points. Cell lysates were subjected to SDS-PAGE and immunoblotted with indicated antibodies.</p></caption><graphic xlink:href="MI2020-6357046.001"></graphic></fig><fig id="fig2" orientation="portrait" position="float"><label>Figure 2</label><caption><p>CD40 expression is not modified by hypoxic stress. (a, b) HK-2 cells were incubated under normoxic or hypoxic conditions during 24 hours and CD40 expression analyzed by RT-qPCR (a) (<italic>n</italic> = 3) or flow cytometry (b) (<italic>n</italic> = 3). (c) HK-2 cells were subjected to different hypoxic times followed by a 24-hour culture in normoxic conditions and CD40 expression analyzed by flow cytometry (<italic>n</italic> = 3, <sup>∗</sup>significant relatively to normoxic control).</p></caption><graphic xlink:href="MI2020-6357046.002"></graphic></fig><fig id="fig3" orientation="portrait" position="float"><label>Figure 3</label><caption><p>HK-2 cells are tolerant to hypoxic challenge. HK-2 cells were subjected to a hypoxic stress for 24 hours and cell viability assayed by measuring annexin-positive cells (a) (<italic>n</italic> = 3, <sup>∗</sup>significant relatively to control) (positive control: cells treated with anti-Fas antibody 1 <italic>μ</italic>g/mL) or LDH release assay (b) (<italic>n</italic> = 4, <sup>∗</sup>significant relatively to control) (positive control from the LDH cytotoxicity assay kit). (c) Hypoxia mitigates HK-2 cell growth. HK-2 cells were plated at various densities, cultures performed under hypoxic or normoxic conditions and cells counted.</p></caption><graphic xlink:href="MI2020-6357046.003"></graphic></fig><fig id="fig4" orientation="portrait" position="float"><label>Figure 4</label><caption><p>Induction of HIF-1<italic>α</italic> and HIF-2<italic>α</italic> and endoplasmic reticulum stress in HK-2 cells grown under hypoxic conditions; (a) HIF-1<italic>α</italic> and HIF-2<italic>α</italic> are induced in response to hypoxic stress. Top panel: HK-2 cells were grown under hypoxic conditions for the indicated times and immunoblotting with anti-HIF-1<italic>α</italic> or anti-HIF-2<italic>α</italic> antibodies performed on cell lysates (<italic>β</italic>-tubulin was used as loading controls); bottom panels: cells were grown under hypoxic conditions for the indicated times in the presence or not of 100 ng/mL rsCD154 and immunoblotting with anti-HIF-1<italic>α</italic> antibody performed on cell lysates (calnexin (CNX) was used as loading controls). (b) VEGF concentration increases in HK-2 cell supernatants in response to hypoxic stress. VEGF was quantified by ELISA in supernatants of HK-2 cells grown under hypoxic or normoxic conditions (<italic>n</italic> = 3, <sup>∗</sup>significant relatively to normoxic control; UD: undetectable levels). (c) Hypoxia induces time-dependent endoplasmic reticulum stress features in HK-2 cells. HK-2 cells were grown under hypoxic conditions for the indicated times and immunoblotting with antibodies against BiP, eIF2<italic>α</italic>, and Phospho-eIF2<italic>α</italic> (P-eIF2<italic>α</italic>) performed on cell lysates (calnexin (CNX) was used as a loading control). (d) Fold induction of the spliced/unspliced ratio of <italic>XBP-1</italic> (<italic>XBP1</italic> s<italic>/u</italic>) mRNA in HK-2 cells grown under hypoxic conditions for the indicated times in the presence or absence of rsCD154 (<italic>n</italic> = 3, <sup>∗</sup>significant relatively to time 0).</p></caption><graphic xlink:href="MI2020-6357046.004"></graphic></fig><fig id="fig5" orientation="portrait" position="float"><label>Figure 5</label><caption><p>CD154 stimulates early IL-6 production by HK-2 cells under hypoxic conditions. (a) HK-2 cells were grown under hypoxic conditions for 3 hours in the presence or not of increasing rsCD154 concentrations and IL-6 measured by ELISA in cell culture supernatants (<italic>n</italic> = 3, <sup>∗</sup>significant relatively to control). (b) HK-2 cells were grown under hypoxic conditions for the indicated times in the presence or not (control) of rsCD154 and IL-6 measured by ELISA in cell culture supernatants (<italic>n</italic> = 3, <sup>∗</sup>significant relatively to control). (c) HK-2 cells were grown under hypoxic conditions for 3 or 24 hours, followed by a 24-hour culture in normoxic conditions in the presence or not (control) of rsCD154 and IL-6 measured by ELISA in cell culture supernatants (<italic>n</italic> = 4, <sup>∗</sup>significant relatively to control). (d) HK-2 cells were grown 1 or 3 hours under hypoxic conditions in the presence or not (control) of rsCD154 (control) and IL-6 concentrations measured in cell lysates (<italic>n</italic> = 3; <sup>∗</sup>significant relatively to control).</p></caption><graphic xlink:href="MI2020-6357046.005"></graphic></fig><fig id="fig6" orientation="portrait" position="float"><label>Figure 6</label><caption><p>CD154 induces IL-6 mRNA in HK-2 cells grown under hypoxic conditions. (a) HK-2 cells were grown 3 hours under hypoxic conditions in the presence or absence of rsCD154 and IL-6 mRNA expression analyzed by RT-qPCR. Data are normalized to cells grown in hypoxic conditions in the absence of rsCD154 (<italic>n</italic> = 6; <sup>∗</sup>significant relatively to control condition). (b) HK-2 cells were grown 3 hours under hypoxic conditions in DMEM containing or not rsCD154 and actinomycin D, and IL-6 mRNA expression analyzed by RT-qPCR. Data are normalized to cells grown in control condition (<italic>n</italic> = 6, <sup>∗</sup>significant relatively to control, <sup>∗∗</sup>significant relatively to rsCD154 condition). (c) HK-2 cells were grown 1 hour under hypoxic conditions in the presence or not of rsCD154 and cycloheximide (CHX), cells were lysed, and IL-6 was measured in cell lysates by ELISA (<italic>n</italic> = 4, total protein amount in cell lysates did not differ between conditions; <sup>∗</sup>significant relatively to control, <sup>∗∗</sup>significant relatively to rsCD154 condition). (d) CD154 stimulates <italic>IL-6</italic> gene transcription in hypoxic conditions. HK-2 cells were grown 3 hours under hypoxic conditions in the presence or absence of rsCD154 in DMEM, and a nascent RNA capture assay was used to monitor the change in <italic>de novo</italic> IL-6 mRNA synthesis. Data are normalized to cells grown in hypoxic condition without rsCD154 (<italic>n</italic> = 4, <sup>∗</sup>significant relatively to control).</p></caption><graphic xlink:href="MI2020-6357046.006"></graphic></fig><fig id="fig7" orientation="portrait" position="float"><label>Figure 7</label><caption><p>Chloroquine alleviates the CD154-mediated induction of IL-6 in HK-2 cells. (a) HK-2 cells were preincubated with chloroquine (50 <italic>μ</italic>g/mL) and then incubated for 3 hours at 0.1% O<sub>2</sub> in the presence or not of rsCD154; IL-6 protein was measured by ELISA in the cell culture supernatants (<italic>n</italic> = 6, <sup>∗</sup>significant relatively to control, <sup>∗∗</sup>significant relatively to rsCD154 condition). (b) Dose effect experiments: HK-2 cells were preincubated with the indicated concentrations of chloroquine and then incubated for 3 hours at 0.1% O<sub>2</sub> in the presence or not of rsCD154; IL-6 protein was measured by ELISA in the cell culture supernatants (<italic>n</italic> = 7, <sup>∗</sup>significant relatively to control, <sup>∗∗</sup>significant relatively to rsCD154 condition). (c) HK-2 cells were incubated for 3 hours at 0.1% O<sub>2</sub> in the presence or not of rsCD154, hydrocortisone (HC) and acetylsalicylic acid (ASA), and IL-6 protein measured by ELISA in cell culture supernatants (<italic>n</italic> = 4, <sup>∗</sup>significant relatively to control).</p></caption><graphic xlink:href="MI2020-6357046.007"></graphic></fig></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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