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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>M2-like macrophages contribute to the establishment of immunosuppressive microenvironments through coordinated activation of inflammatory and metabolic programs. Cyclooxygenase-2 (COX2) catalyzes prostaglandin E2 (PGE2) production, whereas arginase-1 (ARG1) hydrolyzes L-arginine (ARG) to ornithine (ORN) and urea. However, the ion channel-dependent mechanisms governing these immunometabolic pathways remain poorly defined. Here, we examined the role of the Ca2+-activated K+ channel KCa3.1 in regulating COX2 and ARG1 in THP-1-derived M2-like macrophages. COX2 and ARG1 were markedly upregulated during M2-like differentiation, whereas pharmacological activation of KCa3.1 with SKA-121 significantly reduced their mRNA and protein expression. KCa3.1 activation also decreased PGE2 production, increased extracellular ARG, and reduced ORN accumulation. Exposure to elevated extracellular K+ concentration ([K+]e) further enhanced COX2 and ARG1 expression, increased PGE2 production, and shifted ARG metabolism toward ORN formation; each of these responses was attenuated by KCa3.1 activation. Pharmacological inhibition of ERK or CREB signaling suppressed both COX2 and ARG1 expression, whereas inhibition of JNK, AP-1, NOX2, or NRF2 had limited effects. CREB2 knockdown similarly reduced COX2 and ARG1 under both basal and elevated [K+]e conditions. These findings demonstrate that KCa3.1 activation negatively regulates COX2- and ARG1-associated immunometabolic programs in THP-1-derived M2-like macrophages and suggest a potential role for KCa3.1 in modulating macrophage-associated inflammatory and metabolic responses.<\/jats:p>","DOI":"10.3390\/ijms27198477","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T09:20:46Z","timestamp":1790155246000},"page":"8477","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Activation of KCa3.1 K+ Channel Suppresses COX2- and ARG1-Dependent Immunosuppressive Metabolic Programs in THP-1-Derived M2-like Macrophages"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0598-0733","authenticated-orcid":false,"given":"Junko","family":"Kajikuri","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"given":"Ayano","family":"Kitahara","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Miki","family":"Matsui","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Yasuhiro","family":"Maeda","sequence":"additional","affiliation":[{"name":"Omics Analysis Laboratory, Open Facility Center, Fujita Health University, Toyoake 470-1192, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Hiroaki","family":"Kito","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1947-0032","authenticated-orcid":false,"given":"Yohei","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Ryo","family":"Otsuka","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5765-0667","authenticated-orcid":false,"given":"Susumu","family":"Ohya","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4557","DOI":"10.1158\/0008-5472.CAN-18-3962","article-title":"The tumor microenvironment innately modulates cancer progression","volume":"79","author":"Hinshaw","year":"2019","journal-title":"Cancer Res."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Ricketts, T.D., Prieto-Dominguez, N., Gowda, P.S., and Ubil, E. 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