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Immunol."],"abstract":"<jats:p>The NLRP3 inflammasome complex is an important mechanism for regulating the release of pro-inflammatory cytokines, IL-1\u03b2 and IL-18, in response to harmful pathogens. Overproduction of pro-inflammatory cytokines has been linked to cryopyrin-associated periodic syndrome, arthritis, and other inflammatory conditions. It has been previously shown that tumor progression locus 2, a serine-threonine kinase, promotes IL-1\u03b2 synthesis in response to LPS stimulation; however, whether TPL2 kinase activity is required during inflammasome priming to promote <jats:italic>Il1b<\/jats:italic> mRNA transcription and\/or during inflammasome activation for IL-1\u03b2 secretion remained unknown. In addition, whether elevated type I interferons, a consequence of either <jats:italic>Tpl2<\/jats:italic> genetic ablation or inhibition of TPL2 kinase activity, decreases IL-1\u03b2 expression or inflammasome function has not been explored. Using LPS-stimulated primary murine bone marrow-derived macrophages, we determined that TPL2 kinase activity is required for transcription of <jats:italic>Il1b<\/jats:italic>, but not <jats:italic>Nlrp3<\/jats:italic>, <jats:italic>Il18<\/jats:italic>, caspase-1 (<jats:italic>Casp1<\/jats:italic>), or gasdermin-D (<jats:italic>Gsdmd<\/jats:italic>) during inflammasome priming. Both <jats:italic>Casp1<\/jats:italic> and <jats:italic>Gsdmd<\/jats:italic> mRNA synthesis decreased in the absence of type I interferon signaling, evidence of crosstalk between type I interferons and the inflammasome. Our results demonstrate that TPL2 kinase activity is differentially required for the expression of inflammasome precursor cytokines and components but is dispensable for inflammasome activation. These data provide the foundation for the further exploration of TPL2 kinase inhibitor as a potential therapeutic in inflammatory diseases.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1496613","type":"journal-article","created":{"date-parts":[[2025,3,18]],"date-time":"2025-03-18T05:23:29Z","timestamp":1742275409000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["TPL2 kinase activity is required for Il1b transcription during LPS priming but dispensable for NLRP3 inflammasome activation"],"prefix":"10.3389","volume":"16","author":[{"given":"Denise L.","family":"Fahey","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Niki","family":"Patel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wendy 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