Activation of KCa3.1 K⁺ Channel Suppresses COX2- and ARG1-Dependent Immunosuppressive Metabolic Programs in THP-1-Derived M₂-like Macrophages.
- 1Department of Pharmacology, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan.
- 2Omics Analysis Laboratory, Open Facility Center, Fujita Health University, Toyoake 470-1192, Japan.
Abstract
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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BibTeX
@article{kajikuri2026activation,
title = {{Activation of KCa3.1 K⁺ Channel Suppresses COX2- and ARG1-Dependent Immunosuppressive Metabolic Programs in THP-1-Derived M₂-like Macrophages.}},
author = {Junko Kajikuri and Ayano Kitahara and Miki Matsui and Yasuhiro Maeda and Hiroaki Kito and Yohei Yamaguchi and Ryo Otsuka and Susumu Ohya},
journal = {International journal of molecular sciences},
year = {2026},
month = sep,
doi = {10.3390/ijms27198477},
url = {https://europepmc.org/article/MED/42883725},
note = {CC BY},
}
RIS
TY - JOUR
TI - Activation of KCa3.1 K⁺ Channel Suppresses COX2- and ARG1-Dependent Immunosuppressive Metabolic Programs in THP-1-Derived M₂-like Macrophages.
AU - Junko Kajikuri
AU - Ayano Kitahara
AU - Miki Matsui
AU - Yasuhiro Maeda
AU - Hiroaki Kito
AU - Yohei Yamaguchi
AU - Ryo Otsuka
AU - Susumu Ohya
PY - 2026
DA - 2026/09/23
JO - International journal of molecular sciences
DO - 10.3390/ijms27198477
UR - https://europepmc.org/article/MED/42883725
AB - 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.
SN - 1422-0067
ER -