Inhibition of CEACAM1 expression in cytokine-activated neutrophils using JAK inhibitors.

IF 2.9 4区医学 Q3 IMMUNOLOGY

BMC Immunology Pub Date : 2024-10-01 DOI:10.1186/s12865-024-00656-6

Haruki Matsumoto, Ryota Sudo, Yuya Fujita, Michio Onizawa, Kenji Saito, Yuya Sumichika, Shuhei Yoshida, Jumpei Temmoku, Naoki Matsuoka, Tomoyuki Asano, Shuzo Sato, Eiji Suzuki, Takeshi Machida, Kiyoshi Migita

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引用次数: 0

Abstract

Objectives: Carcinoembryonic-antigen-related cell-adhesion molecule 1 (CEACAM1) is an adhesion molecule that acts as a coinhibitory receptor in the immune system. We previously demonstrated that CEACAM1 is predominantly expressed on peripheral blood neutrophils in patients with RA. The aim of the present study was to investigate the effects of Janus kinase inhibitors (JAKi) on cytokine-activated human neutrophils and CEACAM1 expression.

Methods: Peripheral blood neutrophils were obtained from healthy subjects. Isolated neutrophils were stimulated with tumor necrosis factor-alpha (TNF-α) or granulocyte-macrophage colony-stimulating factor (GM-CSF) in the presence or absence of JAKi. The expression of CEACAM1 in peripheral blood neutrophils was analyzed by flow cytometry. Protein phosphorylation of signal transducer and activator of transcription (STAT)1, STAT3, and STAT5 was assessed by western blot using phospho-specific antibodies.

Results: We found that TNF-α-induced CEACAM1 expression was marginally suppressed after pretreatment with pan-JAK inhibitor, tofacitinib. Moreover, TNF-α induced STAT1 and STAT3 phosphorylation at the late stimulation phase (4 to 16 h). The expressions of CEACAM1 on neutrophils were markedly up-regulated by GM-CSF not by interleukin (IL)-6 stimulation. All JAKi inhibited GM-CSF-induced CEACAM1 expressions on neutrophils, however, the inhibitory effects of baricitinib were larger compared to those of tofacitinib or filgotinib. Moreover, CEACAM1 was marginally upregulated in interferon (IFN)-γ stimulated neutrophils. Similarly, JAKi inhibited IFN-γ-induced CEACAM1 expressions on neutrophils.

Conclusions: We demonstrated that JAKi prevent GM-CSF-induced CEACAM1 expression in neutrophils, and JAKi-induced inhibition depends on their selectivity against JAK isoforms. These findings suggest that JAKi can modulate the expression of CEACAM1 in cytokine-activated neutrophils, thereby limiting their activation.

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使用 JAK 抑制剂抑制细胞因子激活的中性粒细胞中 CEACAM1 的表达。

研究目的癌胚抗原相关细胞粘附分子 1（CEACAM1）是一种粘附分子，在免疫系统中充当共抑制受体。我们曾证实 CEACAM1 主要表达于 RA 患者的外周血中性粒细胞。本研究旨在探讨Janus激酶抑制剂（JAKi）对细胞因子激活的人中性粒细胞和CEACAM1表达的影响：方法：从健康受试者处获取外周血中性粒细胞。在有或没有 JAKi 的情况下，用肿瘤坏死因子-α（TNF-α）或粒细胞-巨噬细胞集落刺激因子（GM-CSF）刺激分离的中性粒细胞。流式细胞术分析了外周血中性粒细胞中 CEACAM1 的表达。使用磷酸化特异性抗体通过 Western 印迹评估信号转导和转录激活因子（STAT）1、STAT3 和 STAT5 的蛋白磷酸化：结果：我们发现，TNF-α诱导的CEACAM1表达在使用泛JAK抑制剂托法替尼预处理后略有抑制。此外，TNF-α在刺激后期（4-16 h）诱导STAT1和STAT3磷酸化。中性粒细胞上的 CEACAM1 的表达在 GM-CSF 而非白细胞介素（IL）-6 的刺激下明显上调。所有JAKi都能抑制GM-CSF诱导的CEACAM1在中性粒细胞上的表达，但巴利昔替尼的抑制作用大于托法替尼和非格替尼。此外，CEACAM1在干扰素（IFN）-γ刺激的中性粒细胞中略有上调。同样，JAKi抑制了IFN-γ诱导的中性粒细胞上CEACAM1的表达：我们证实，JAKi能阻止GM-CSF诱导的CEACAM1在中性粒细胞中的表达，而JAKi诱导的抑制作用取决于其对JAK同工酶的选择性。这些发现表明，JAKi 可调节细胞因子激活的中性粒细胞中 CEACAM1 的表达，从而限制其活化。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

BMC Immunology 医学-免疫学

CiteScore

5.50

自引率

0.00%

发文量

审稿时长

1 months

期刊介绍： BMC Immunology is an open access journal publishing original peer-reviewed research articles in molecular, cellular, tissue-level, organismal, functional, and developmental aspects of the immune system as well as clinical studies and animal models of human diseases.