STAT1- and NFAT-independent amplification of purinoceptor function integrates cellular senescence with interleukin-6 production in preadipocytes

Majeed, Yasser, Madani, Aisha Y., Altamimi, Ahmed I., Courjaret, Raphael, Vakayil, Muneera, Fountain, Samuel J. ORCID:, Machaca, Khaled and Mazloum, Nayef A. (2023) STAT1- and NFAT-independent amplification of purinoceptor function integrates cellular senescence with interleukin-6 production in preadipocytes. British Journal of Pharmacology, 180 (5). pp. 609-627. ISSN 0007-1188

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Background and Purpose: 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. Experimental Approach: 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. Key Results: DNA damage-induced senescence up-regulated purinoceptor expression levels in preadipocytes and MS1 VEGF angiosarcoma cells. ATP-evoked Ca 2+ 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 A 3 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 P2Y 12–P2Y 13 receptors to downstream interleukin-6 production. Interleukin-6 signalling exacerbated inflammation during senescence and compromised adipogenesis. Conclusions and Implications: 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.

Item Type: Article
Additional Information: Funding information: This publication was made possible by a National Priorities Research Program grant (NPRP10-1205-160010) awarded to NAM by the Qatar National Research Fund (QNRF) and Biomedical Research Program (BMRP) funds at Weill Cornell Medicine-Qatar (WCM-Q), a programme funded by Qatar Foundation. AYM was supported by a Graduate Student Research Award (GSRA4-1-0330-17010) from the QNRF. AIA was supported by an Undergraduate Research Experience Program grant (UREP25-026-3-005) awarded by the QNRF and by a Student Research Mentorship Program grant (SRMP 003-01) awarded by WCM-Q. Open access funding was provided by the Qatar National Library. The statements made herein are solely the responsibility of the authors.
Uncontrolled Keywords: adora3,dna damage,inflammation,interleukin-6,purinergic signalling,senescence,pharmacology ,/dk/atira/pure/subjectarea/asjc/3000/3004
Faculty \ School: Faculty of Science > School of Biological Sciences
UEA Research Groups: Faculty of Science > Research Groups > Cells and Tissues
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Depositing User: LivePure Connector
Date Deposited: 14 Oct 2022 11:33
Last Modified: 19 Apr 2023 01:15
DOI: 10.1111/bph.15978


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