Taniguchi Kosuke, Hikiji Hisako, Okinaga Toshinori, Hashidate-Yoshida Tomomi, Shindou Hideo, Ariyoshi Wataru, Shimizu Takao, Tominaga Kazuhiro, Nishihara Tatsuji
Division of Infections and Molecular Biology, Department of Health Promotion, Kyushu Dental University, Kitakyushu, Fukuoka, 803-8580, Japan.
Division of Oral and Maxillofacial Surgery, Department of Science of Physical Function, Kyushu Dental University, Kitakyushu, Fukuoka, 803-8580, Japan.
J Cell Biochem. 2015 Dec;116(12):2840-8. doi: 10.1002/jcb.25230.
Lysophospholipid acyltransferases (LPLATs) regulate the diversification of fatty acid composition in biological membranes. Lysophosphatidylcholine acyltransferases (LPCATs) are members of the LPLATs that play a role in inflammatory responses. M1 macrophages differentiate in response to lipopolysaccharide (LPS) and are pro-inflammatory, whereas M2 macrophages, which differentiate in response to interleukin-4 (IL-4), are anti-inflammatory and involved in homeostasis and wound healing. In the present study, we showed that LPCATs play an important role in M1/M2-macrophage polarization. LPS changed the shape of PMA-treated U937 cells from rounded to spindle shaped and upregulated the mRNA and protein expression of the M1 macrophage markers CXCL10, TNF-α, and IL-1β. IL-4 had no effect on the shape of PMA-treated U937 cells and upregulated the M2 macrophage markers CD206, IL-1ra, and TGF-β in PMA-treated U937 cells. These results suggest that LPS and IL-4 promote the differentiation of PMA-treated U937 cells into M1- and M2-polarized macrophages, respectively. LPS significantly downregulated the mRNA expression of LPCAT3, one of four LPCAT isoforms, and suppressed its enzymatic activity toward linoleoyl-CoA and arachidonoyl-CoA in PMA-treated U937 cells. LPCAT3 knockdown induced a spindle-shaped morphology typical of M1-polarized macrophages, and increased the secretion of CXCL10 and decreased the levels of CD206 in IL-4-activated U937 cells. This indicates that knockdown of LPCAT3 shifts the differentiation of PMA-treated U937 cells to M1-polarized macrophages. Our findings suggest that LPCAT3 plays an important role in M1/M2-macrophage polarization, providing novel potential therapeutic targets for the regulation of immune and inflammatory disorders.
溶血磷脂酰基转移酶（LPLATs）调节生物膜中脂肪酸组成的多样化。溶血磷脂酰胆碱酰基转移酶（LPCATs）是LPLATs的成员，在炎症反应中发挥作用。M1巨噬细胞响应脂多糖（LPS）而分化，具有促炎作用，而响应白细胞介素-4（IL-4）分化的M2巨噬细胞具有抗炎作用，参与体内平衡和伤口愈合。在本研究中，我们表明LPCATs在M1/M2巨噬细胞极化中起重要作用。LPS使经佛波酯（PMA）处理的U937细胞形状从圆形变为纺锤形，并上调M1巨噬细胞标志物CXCL10、肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β）的mRNA和蛋白质表达。IL-4对经PMA处理的U937细胞形状没有影响，但上调了经PMA处理的U937细胞中M2巨噬细胞标志物CD206、白细胞介素-1受体拮抗剂（IL-1ra）和转化生长因子-β（TGF-β）的表达。这些结果表明，LPS和IL-4分别促进经PMA处理的U937细胞分化为M1极化和M2极化的巨噬细胞。LPS显著下调四种LPCAT同工型之一的LPCAT3的mRNA表达，并抑制其在经PMA处理的U937细胞中对亚油酰辅酶A和花生四烯酰辅酶A的酶活性。敲低LPCAT3诱导出M1极化巨噬细胞典型的纺锤形形态，并增加了CXCL10的分泌，降低了IL-4激活的U937细胞中CD206的水平。这表明敲低LPCAT3使经PMA处理的U937细胞的分化转向M1极化巨噬细胞。我们的研究结果表明，LPCAT3在M1/M2巨噬细胞极化中起重要作用，为调节免疫和炎症性疾病提供了新的潜在治疗靶点。
