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Our previous studies suggested a novel role for CES1 in the regulation of macrophage gene expression following exposure to inflammatory molecules. The nuclear receptor PPAR\u03b3 has an important role in the M(IL-4) polarization response. Here, we investigated CES1 in human primary macrophages and THP-1 macrophages during M(IL-4) polarization. We hypothesized that ablating CES1's activity would decrease ligand signaling through PPAR\u03b3, thereby reducing the M2 polarization response. Inhibition of CES1's activity by small-molecule inhibitors (WWL113 or WWL229) attenuated the mRNA expression of several IL-4-induced M2 markers, including ALOX15. Similar results were found in macrophages in which CES1 or PPARg expression was silenced. Immunoblot and mass spectrometric analyses indicated that IL-4-induced ALOX15 and its enzymatic product, 15-hydroxyeicosatetraenoic acid, were both reduced by CES1 inhibition. Further, a PPAR\u03b3 antagonist (GW9662) also altered the profile of IL-4-induced M2 markers. The M(IL-4)-induced increase in endogenous PPAR\u03b3 ligands was augmented by WWL113. Surprisingly, PPAR\u03b3 agonist \u201cadd-back\u201d strengthened the WWL113-mediated repression of IL-4-induced ALOX15 expression, whereas IL-4-induced FABP4 mRNA levels were augmented. Collectively, these results suggest that CES1 has a complex role in driving the alternative activation phenotype in response to IL-4, possibly through an ability to influence PPAR\u03b3. These findings are consistent with previous work in which CES1 appeared to hold in check the inflammatory response of innate immune cells. The significance of our findings is that CES1 appears to contribute to the integration of extracellular signals that shape macrophage phenotypes.<\/jats:p>","DOI":"10.1093\/jleuko\/qiag073","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T11:32:17Z","timestamp":1781004737000},"source":"Crossref","is-referenced-by-count":0,"title":["Carboxylesterase 1 contributes to the human macrophage alternative activation response to Th2 cytokine interleukin-4"],"prefix":"10.1093","volume":"118","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9167-8452","authenticated-orcid":false,"given":"Matthew K","family":"Ross","sequence":"first","affiliation":[{"name":"Department of Comparative Biomedical Sciences, College of Veterinary Medicine, P.O. Box 6100, Mississippi State University , Mississippi State, Mississippi 39762 ,","place":["United States"]},{"name":"Center for Environmental Health Sciences, College of Veterinary Medicine, P.O. Box 6100, Mississippi State University , Mississippi State, Mississippi 39762 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdolsamad","family":"Borazjani","sequence":"additional","affiliation":[{"name":"Department of Comparative Biomedical Sciences, College of Veterinary Medicine, P.O. Box 6100, Mississippi State University , Mississippi State, Mississippi 39762 ,","place":["United States"]},{"name":"Center for Environmental Health Sciences, College of Veterinary Medicine, P.O. Box 6100, Mississippi State University , Mississippi State, Mississippi 39762 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah L","family":"Thrash","sequence":"additional","affiliation":[{"name":"Department of Comparative Biomedical Sciences, College of Veterinary Medicine, P.O. Box 6100, Mississippi State University , Mississippi State, Mississippi 39762 ,","place":["United States"]},{"name":"Center for Environmental Health Sciences, College of Veterinary Medicine, P.O. Box 6100, Mississippi State University , Mississippi State, Mississippi 39762 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oluwabori","family":"Adekanye","sequence":"additional","affiliation":[{"name":"Department of Comparative Biomedical Sciences, College of Veterinary Medicine, P.O. Box 6100, Mississippi State University , Mississippi State, Mississippi 39762 ,","place":["United States"]},{"name":"Center for Environmental Health Sciences, College of Veterinary Medicine, P.O. Box 6100, Mississippi State University , Mississippi State, Mississippi 39762 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J Allen","family":"Crow","sequence":"additional","affiliation":[{"name":"Department of Comparative Biomedical Sciences, College of Veterinary Medicine, P.O. Box 6100, Mississippi State University , Mississippi State, Mississippi 39762 ,","place":["United States"]},{"name":"Center for Environmental Health Sciences, College of Veterinary Medicine, P.O. Box 6100, Mississippi State University , Mississippi State, Mississippi 39762 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,6,10]]},"reference":[{"key":"2026062905114809800_qiag073-B1","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1126\/science.1230720","article-title":"Anti-inflammatory therapy in chronic disease: challenges and opportunities","volume":"339","author":"Tabas","year":"2013","journal-title":"Science"},{"key":"2026062905114809800_qiag073-B2","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1146\/annurev-physiol-022516-034339","article-title":"Macrophage polarization","volume":"79","author":"Murray","year":"2017","journal-title":"Annu Rev Physiol."},{"key":"2026062905114809800_qiag073-B3","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1172\/JCI59643","article-title":"Macrophage plasticity and polarization: in vivo 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