STAT1‐ and NFAT‐independent amplification of purinoceptor function integrates cellular senescence with interleukin‐6 production in preadipocytes
<div><h2>Background and Purpose</h2> <p>Senescent preadipocytes promote adipose tissue dysfunction by secreting pro‐inflammatory factors, although little is known about the mechanisms regulating their production. We investigated if up‐regulated purinoceptor function sensitize...
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| المؤلف الرئيسي: | |
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| مؤلفون آخرون: | , , , , , , |
| منشور في: |
2022
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| الموضوعات: | |
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| _version_ | 1864513512738390016 |
|---|---|
| author | Yasser Majeed (9417974) |
| author2 | Aisha Y. Madani (14152911) Ahmed I. Altamimi (18811030) Raphael Courjaret (9592368) Muneera Vakayil (12037693) Samuel J. Fountain (18811033) Khaled Machaca (194372) Nayef A. Mazloum (7355087) |
| author2_role | author author author author author author author |
| author_facet | Yasser Majeed (9417974) Aisha Y. Madani (14152911) Ahmed I. Altamimi (18811030) Raphael Courjaret (9592368) Muneera Vakayil (12037693) Samuel J. Fountain (18811033) Khaled Machaca (194372) Nayef A. Mazloum (7355087) |
| author_role | author |
| dc.creator.none.fl_str_mv | Yasser Majeed (9417974) Aisha Y. Madani (14152911) Ahmed I. Altamimi (18811030) Raphael Courjaret (9592368) Muneera Vakayil (12037693) Samuel J. Fountain (18811033) Khaled Machaca (194372) Nayef A. Mazloum (7355087) |
| dc.date.none.fl_str_mv | 2022-11-02T03:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1111/bph.15978 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/STAT1_and_NFAT_independent_amplification_of_purinoceptor_function_integrates_cellular_senescence_with_interleukin_6_production_in_preadipocytes/26021659 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biological sciences Biochemistry and cell biology Microbiology Biomedical and clinical sciences Immunology Medical physiology Adora3 DNA damage inflammation nterleukin-6 urinergic signalling enescence |
| dc.title.none.fl_str_mv | STAT1‐ and NFAT‐independent amplification of purinoceptor function integrates cellular senescence with interleukin‐6 production in preadipocytes |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <div><h2>Background and Purpose</h2> <p>Senescent preadipocytes promote adipose tissue dysfunction by secreting pro‐inflammatory factors, although little is known about the mechanisms regulating their production. We investigated if up‐regulated purinoceptor function sensitizes senescent preadipocytes to cognate agonists and how such sensitization regulates inflammation.</p> <h2>Experimental Approach</h2> <p>Etoposide was used to trigger senescence in 3T3‐L1 preadipocytes. CRISPR/Cas9 technology or pharmacology allowed studies of transcription factor function. Fura‐2 imaging was used for calcium measurements. Interleukin‐6 levels were quantified using quantitative PCR and ELISA. Specific agonists and antagonists supported studies of purinoceptor coupling to interleukin‐6 production. Experiments in MS1 VEGF angiosarcoma cells and adipose tissue samples from obese mice complemented preadipocyte experiments.</p> <h2>Key Results</h2> <p>DNA damage‐induced senescence up‐regulated purinoceptor expression levels in preadipocytes and MS1 VEGF angiosarcoma cells. ATP‐evoked Ca2+ release was potentiated in senescent preadipocytes. ATP enhanced interleukin‐6 production, an effect mimicked by ADP but not UTP, in a calcium‐independent manner. Senescence‐associated up‐regulation and activation of the adenosine A3 receptor also enhanced interleukin‐6 production. However, nucleotide hydrolysis was not essential because exposure to ATPγS also enhanced interleukin‐6 secretion. Pharmacological experiments suggested coupling of P2X ion channels and P2Y12–P2Y13 receptors to downstream interleukin‐6 production. Interleukin‐6 signalling exacerbated inflammation during senescence and compromised adipogenesis.</p> <h2>Conclusions and Implications</h2> <p>We report a previously uncharacterized link between cellular senescence and purinergic signalling in preadipocytes and endothelial cancer cells, raising the possibility that up‐regulated purinoceptors play key modulatory roles in senescence‐associated conditions like obesity and cancer. There is potential for exploitation of specific purinoceptor antagonists as therapeutics in inflammatory disorders.</p> </div><h2>Other Information</h2> <p> Published in: British Journal of Pharmacology<br> License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1111/bph.15978" target="_blank">https://dx.doi.org/10.1111/bph.15978</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_fd6f35319b6e7c534e9e63bf4eb3c13f |
| identifier_str_mv | 10.1111/bph.15978 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/26021659 |
| publishDate | 2022 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | STAT1‐ and NFAT‐independent amplification of purinoceptor function integrates cellular senescence with interleukin‐6 production in preadipocytesYasser Majeed (9417974)Aisha Y. Madani (14152911)Ahmed I. Altamimi (18811030)Raphael Courjaret (9592368)Muneera Vakayil (12037693)Samuel J. Fountain (18811033)Khaled Machaca (194372)Nayef A. Mazloum (7355087)Biological sciencesBiochemistry and cell biologyMicrobiologyBiomedical and clinical sciencesImmunologyMedical physiologyAdora3DNA damageinflammationnterleukin-6urinergic signallingenescence<div><h2>Background and Purpose</h2> <p>Senescent preadipocytes promote adipose tissue dysfunction by secreting pro‐inflammatory factors, although little is known about the mechanisms regulating their production. We investigated if up‐regulated purinoceptor function sensitizes senescent preadipocytes to cognate agonists and how such sensitization regulates inflammation.</p> <h2>Experimental Approach</h2> <p>Etoposide was used to trigger senescence in 3T3‐L1 preadipocytes. CRISPR/Cas9 technology or pharmacology allowed studies of transcription factor function. Fura‐2 imaging was used for calcium measurements. Interleukin‐6 levels were quantified using quantitative PCR and ELISA. Specific agonists and antagonists supported studies of purinoceptor coupling to interleukin‐6 production. Experiments in MS1 VEGF angiosarcoma cells and adipose tissue samples from obese mice complemented preadipocyte experiments.</p> <h2>Key Results</h2> <p>DNA damage‐induced senescence up‐regulated purinoceptor expression levels in preadipocytes and MS1 VEGF angiosarcoma cells. ATP‐evoked Ca2+ release was potentiated in senescent preadipocytes. ATP enhanced interleukin‐6 production, an effect mimicked by ADP but not UTP, in a calcium‐independent manner. Senescence‐associated up‐regulation and activation of the adenosine A3 receptor also enhanced interleukin‐6 production. However, nucleotide hydrolysis was not essential because exposure to ATPγS also enhanced interleukin‐6 secretion. Pharmacological experiments suggested coupling of P2X ion channels and P2Y12–P2Y13 receptors to downstream interleukin‐6 production. Interleukin‐6 signalling exacerbated inflammation during senescence and compromised adipogenesis.</p> <h2>Conclusions and Implications</h2> <p>We report a previously uncharacterized link between cellular senescence and purinergic signalling in preadipocytes and endothelial cancer cells, raising the possibility that up‐regulated purinoceptors play key modulatory roles in senescence‐associated conditions like obesity and cancer. There is potential for exploitation of specific purinoceptor antagonists as therapeutics in inflammatory disorders.</p> </div><h2>Other Information</h2> <p> Published in: British Journal of Pharmacology<br> License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1111/bph.15978" target="_blank">https://dx.doi.org/10.1111/bph.15978</a></p>2022-11-02T03:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1111/bph.15978https://figshare.com/articles/journal_contribution/STAT1_and_NFAT_independent_amplification_of_purinoceptor_function_integrates_cellular_senescence_with_interleukin_6_production_in_preadipocytes/26021659CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/260216592022-11-02T03:00:00Z |
| spellingShingle | STAT1‐ and NFAT‐independent amplification of purinoceptor function integrates cellular senescence with interleukin‐6 production in preadipocytes Yasser Majeed (9417974) Biological sciences Biochemistry and cell biology Microbiology Biomedical and clinical sciences Immunology Medical physiology Adora3 DNA damage inflammation nterleukin-6 urinergic signalling enescence |
| status_str | publishedVersion |
| title | STAT1‐ and NFAT‐independent amplification of purinoceptor function integrates cellular senescence with interleukin‐6 production in preadipocytes |
| title_full | STAT1‐ and NFAT‐independent amplification of purinoceptor function integrates cellular senescence with interleukin‐6 production in preadipocytes |
| title_fullStr | STAT1‐ and NFAT‐independent amplification of purinoceptor function integrates cellular senescence with interleukin‐6 production in preadipocytes |
| title_full_unstemmed | STAT1‐ and NFAT‐independent amplification of purinoceptor function integrates cellular senescence with interleukin‐6 production in preadipocytes |
| title_short | STAT1‐ and NFAT‐independent amplification of purinoceptor function integrates cellular senescence with interleukin‐6 production in preadipocytes |
| title_sort | STAT1‐ and NFAT‐independent amplification of purinoceptor function integrates cellular senescence with interleukin‐6 production in preadipocytes |
| topic | Biological sciences Biochemistry and cell biology Microbiology Biomedical and clinical sciences Immunology Medical physiology Adora3 DNA damage inflammation nterleukin-6 urinergic signalling enescence |