{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T07:12:48Z","timestamp":1791443568048,"version":"4.3.3"},"reference-count":74,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,11,19]],"date-time":"2021-11-19T00:00:00Z","timestamp":1637280000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003286","name":"Kuwait Foundation for the Advancement of Sciences","doi-asserted-by":"publisher","award":["RA AH 2016-007"],"award-info":[{"award-number":["RA AH 2016-007"]}],"id":[{"id":"10.13039\/501100003286","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>IL-6 was found to be overexpressed in the adipose tissue of obese individuals, which may cause insulin resistance. However, the regulation of IL-6 in adipocytes in obesity setting remains to be explored. Since IL-1\u03b2 and TNF\u03b1 are increased in obese adipose tissue and promote inflammation, we investigated whether cooperation between IL-1\u03b2 and TNF\u03b1 influences the production of IL-6. Our data show that IL-1\u03b2 and TNF\u03b1 cooperatively enhance IL-6 expression in 3T3L-1 adipocytes. Similar results were seen in human adipocytes isolated from subcutaneous and visceral fat. Although adipocytes isolated from lean and obese adipose tissues showed similar responses for production of IL-6 when incubated with IL-1\u03b2\/TNF\u03b1, secretion of IL-6 was higher in adipocytes from obese tissue. TNF\u03b1 treatment enhanced CREB binding at CRE locus, which was further enhanced with IL-1\u03b2, and was associated with elevated histone acetylation at CRE locus. On the other hand, IL-1\u03b2 treatments mediated C\/EBP\u03b2 binding to NF-IL-6 consensus, but not sufficiently to mediate significant histone acetylation. Interestingly, treatment with both stimulatory factors amplifies CREB binding and H3K14 acetylation. Furthermore, histone acetylation inhibition by anacardic acid or curcumin reduces IL-6 production. Notably, inhibition of histone deacetylase (HDAC) activity by trichostatin A (TSA) resulted in the further elevation of IL-6 expression in response to combined treatment of adipocytes with IL-1\u03b2 and TNF\u03b1. In conclusion, our results show that there is an additive interaction between IL-1\u03b2 and TNF\u03b1 that depends on CREB binding and H3K14 acetylation, and leads to the elevation of IL-6 expression in adipocytes, providing interesting pathophysiological connection among IL-1\u03b2, TNF\u03b1, and IL-6 in settings such as obesity.<\/jats:p>","DOI":"10.3390\/cells10113228","type":"journal-article","created":{"date-parts":[[2021,11,19]],"date-time":"2021-11-19T02:43:09Z","timestamp":1637289789000},"page":"3228","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":59,"title":["IL-1\u03b2 and TNF\u03b1 Cooperativity in Regulating IL-6 Expression in Adipocytes Depends on CREB Binding and H3K14 Acetylation"],"prefix":"10.3390","volume":"10","author":[{"given":"Areej","family":"Al-Roub","sequence":"first","affiliation":[{"name":"Immunology & Microbiology Department, Dasman Diabetes Institute, Dasman 15462, Kuwait"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8593-3878","authenticated-orcid":false,"given":"Ashraf","family":"Al Madhoun","sequence":"additional","affiliation":[{"name":"Genetics & Bioinformatics, Dasman Diabetes Institute, Dasman 15462, Kuwait"},{"name":"Animal and Imaging Core Facilities, Dasman Diabetes Institute, Dasman 15462, Kuwait"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadeem","family":"Akhter","sequence":"additional","affiliation":[{"name":"Immunology & Microbiology Department, Dasman Diabetes Institute, Dasman 15462, Kuwait"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9933-0285","authenticated-orcid":false,"given":"Reeby","family":"Thomas","sequence":"additional","affiliation":[{"name":"Immunology & Microbiology Department, Dasman Diabetes Institute, Dasman 15462, Kuwait"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lavina","family":"Miranda","sequence":"additional","affiliation":[{"name":"Genetics & Bioinformatics, Dasman Diabetes Institute, Dasman 15462, Kuwait"},{"name":"Animal and Imaging Core Facilities, Dasman Diabetes Institute, Dasman 15462, Kuwait"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Texy","family":"Jacob","sequence":"additional","affiliation":[{"name":"Immunology & Microbiology Department, Dasman Diabetes Institute, Dasman 15462, Kuwait"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ebaa","family":"Al-Ozairi","sequence":"additional","affiliation":[{"name":"Medical Division, Dasman Diabetes Institute, Dasman 15462, Kuwait"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5409-3829","authenticated-orcid":false,"given":"Fahd","family":"Al-Mulla","sequence":"additional","affiliation":[{"name":"Genetics & Bioinformatics, Dasman Diabetes Institute, Dasman 15462, Kuwait"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9936-1575","authenticated-orcid":false,"given":"Sardar","family":"Sindhu","sequence":"additional","affiliation":[{"name":"Immunology & Microbiology Department, Dasman Diabetes Institute, Dasman 15462, Kuwait"},{"name":"Animal and Imaging Core Facilities, Dasman Diabetes Institute, Dasman 15462, Kuwait"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5746-0743","authenticated-orcid":false,"given":"Rasheed","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Immunology & Microbiology Department, Dasman Diabetes Institute, Dasman 15462, Kuwait"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1016\/S0140-6736(14)60460-8","article-title":"Global, regional, and national prevalence of overweight and obesity in children and adults during 1980\u20132013: A systematic analysis for the global burden of disease study 2013","volume":"384","author":"Ng","year":"2014","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1038\/nri2925","article-title":"Type 2 diabetes as an inflammatory disease","volume":"11","author":"Donath","year":"2011","journal-title":"Nat. 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