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Activation of KCa3.1 K+ Channel Suppresses COX2- and ARG1-Dependent Immunosuppressive Metabolic Programs in THP-1-Derived M2-like Macrophages.

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Τίτλος: Activation of KCa3.1 K+ Channel Suppresses COX2- and ARG1-Dependent Immunosuppressive Metabolic Programs in THP-1-Derived M2-like Macrophages.
Συγγραφείς: Kajikuri J; Department of Pharmacology, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan., Kitahara A; Department of Pharmacology, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan., Matsui M; Department of Pharmacology, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan., Maeda Y; Omics Analysis Laboratory, Open Facility Center, Fujita Health University, Toyoake 470-1192, Japan., Kito H; Department of Pharmacology, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan., Yamaguchi Y; Department of Pharmacology, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan., Otsuka R; Department of Pharmacology, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan., Ohya S; Department of Pharmacology, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan.
Πηγή: International journal of molecular sciences [Int J Mol Sci] 2026 Sep 23; Vol. 27 (19). Date of Electronic Publication: 2026 Sep 23.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE
Imprint Name(s): Original Publication: Basel, Switzerland : MDPI, [2000-
Ιατρικοί όροι (MeSH): Arginase*/metabolism , Arginase*/genetics , Intermediate-Conductance Calcium-Activated Potassium Channels*/metabolism , Intermediate-Conductance Calcium-Activated Potassium Channels*/genetics , Macrophages*/metabolism , Macrophages*/immunology , Cyclooxygenase 2*/metabolism , Cyclooxygenase 2*/genetics, Dinoprostone/metabolism ; Arginine/metabolism ; Humans ; THP-1 Cells ; Cell Differentiation ; Signal Transduction
Περίληψη: 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.
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Grant Information: JP24K09847 Japan Society for the Promotion of Science; JP24K10314 Japan Society for the Promotion of Science; JPMXS0441500024 Ministry of Education, Culture, Sports, Science and Technology; 2324 Salt Science Research Foundation; 2025-23 Aichi Cancer Research Foundation; 2025-19 The Nitto Foundation
Contributed Indexing: Keywords: ARG1; COX2; K+ channel; KCa3.1; M2-like macrophage; PGE2; arginine; elevated extracellular K+ concentration; tumor microenvironment
Substance Nomenclature: EC 3.5.3.1 (Arginase)
0 (Intermediate-Conductance Calcium-Activated Potassium Channels)
EC 1.14.99.1 (Cyclooxygenase 2)
EC 3.5.3.1 (ARG1 protein, human)
0 (KCNN4 protein, human)
K7Q1JQR04M (Dinoprostone)
EC 1.14.99.1 (PTGS2 protein, human)
94ZLA3W45F (Arginine)
Entry Date(s): Date Created: 20261016 Date Completed: 20261016 Latest Revision: 20261020
Update Code: 20261020
PubMed Central ID: PMC13665041
DOI: 10.3390/ijms27198477
PMID: 42883725
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1422-0067
DOI:10.3390/ijms27198477