{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Pharmacology, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan.",
    "Omics Analysis Laboratory, Open Facility Center, Fujita Health University, Toyoake 470-1192, Japan."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Junko Kajikuri",
      "orcid": "0000-0003-0598-0733"
    },
    {
      "affs": [
        0
      ],
      "name": "Ayano Kitahara"
    },
    {
      "affs": [
        0
      ],
      "name": "Miki Matsui"
    },
    {
      "affs": [
        1
      ],
      "name": "Yasuhiro Maeda"
    },
    {
      "affs": [
        0
      ],
      "name": "Hiroaki Kito"
    },
    {
      "affs": [
        0
      ],
      "name": "Yohei Yamaguchi",
      "orcid": "0000-0002-1947-0032"
    },
    {
      "affs": [
        0
      ],
      "name": "Ryo Otsuka"
    },
    {
      "affs": [
        0
      ],
      "name": "Susumu Ohya",
      "orcid": "0000-0002-5765-0667"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/263beev2j9wqd.bib",
  "cited_by": 0,
  "doi": "10.3390/ijms27198477",
  "fulltext_url": "https://europepmc.org/articles/PMC13665041",
  "id": "263beev2j9wqd",
  "issns": [
    "1422-0067"
  ],
  "landing_url": "https://europepmc.org/article/MED/42883725",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2403|Immune cells in cancer"
    ]
  ],
  "openalex": "W7214128145",
  "pdf_url": "https://europepmc.org/articles/PMC13665041?pdf=render",
  "pmcid": "PMC13665041",
  "pmid": "42883725",
  "published": "2026-09-23",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/263beev2j9wqd.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:16Z",
      "native_id": "MED:42883725",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42883725"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2403|Immune cells in cancer",
      "subfield": "immunology"
    }
  ],
  "title": "Activation of KCa3.1 K⁺ Channel Suppresses COX2- and ARG1-Dependent Immunosuppressive Metabolic Programs in THP-1-Derived M₂-like Macrophages.",
  "title_text": "Activation of KCa3.1 K⁺ Channel Suppresses COX2- and ARG1-Dependent Immunosuppressive Metabolic Programs in THP-1-Derived M₂-like Macrophages.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:16Z",
  "url": "https://research.draconitic.com/paper/263beev2j9wqd",
  "venue": "International journal of molecular sciences",
  "versions": []
}