Guo Fang, He Hui, Fu Zhi-Chao, Huang Shengping, Chen Tingtao, Papasian Christopher J, Morse Leslie R, Xu Yan, Battaglino Ricardo A, Yang Xiao-Feng, Jiang Zhisheng, Xin Hong-Bo, Fu Mingui
Department of Pathophysiology, The Institute of Cardiovascular Disease, University of South China, Hengyang, Hunan 421001, China Department of Basic Medical Science, School of Medicine, University of Missouri Kansas City, Kansas City, MO 64108, U.S.A.
Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi 330031, China.
Biochem J. 2015 Dec 15;472(3):309-18. doi: 10.1042/BJ20150019. Epub 2015 Oct 5.
Macrophages within adipose tissue play a key role in mediating inflammatory responses in adipose tissue that are associated with obesity-related metabolic complications. In an effort to identify novel proteins secreted from adipocytes that may negatively regulate macrophage inflammation, we found that peroxiredoxin (PRX)-like 2 activated in M-CSF stimulated monocytes (PAMM), a CXXC-type PRX-like 2 domain-containing redox regulatory protein, is a novel secreted protein with potent anti-inflammatory properties. PAMM is secreted from mature human adipocytes but not preadipocytes. Overexpression of PAMM significantly attenuated lipopolysaccharide (LPS)-induced macrophage inflammation. Incubation of macrophages with adipocyte-conditional medium treated with anti-PAMM antibody significantly enhanced LPS-induced interleukin-12 (IL-12) expression in Raw264.7 cells. In addition, incubation of Raw264.7 cells with purified PAMM protein had a similar anti-inflammatory effect. Moreover, forced expression of PAMM in Raw264.7 cells resulted in decreased LPS-induced ERK1/2, p38 and c-Jun N-terminal kinase (JNK) phosphorylation, suggesting that PAMM exerted the anti-inflammatory function probably by suppressing the mitogen-activated protein kinase (MAPK) signalling pathway. Mutations in the CXXC motif of PAMM that suppressed its anti-redox activity were still able to suppress production of inflammatory cytokines in LPS-stimulated macrophages, suggesting that PAMM's anti-inflammatory properties may be independent of its antioxidant properties. Finally, PAMM was highly expressed in both white (WAT) and brown adipose tissues (BAT) and further increased in obesity status. Our results suggest that adipocyte-derived PAMM may suppress macrophage activation by inhibiting MAPK signalling pathway.
脂肪组织中的巨噬细胞在介导与肥胖相关代谢并发症相关的脂肪组织炎症反应中起关键作用。为了鉴定可能对巨噬细胞炎症起负调节作用的脂肪细胞分泌的新蛋白质，我们发现过氧化物酶体增殖物激活受体（PRX）样2在M-CSF刺激的单核细胞（PAMM）中被激活，PAMM是一种含CXXC型PRX样2结构域的氧化还原调节蛋白，是一种具有强大抗炎特性的新型分泌蛋白。PAMM由成熟的人类脂肪细胞而非前脂肪细胞分泌。PAMM的过表达显著减轻了脂多糖（LPS）诱导的巨噬细胞炎症。用抗PAMM抗体处理的脂肪细胞条件培养基孵育巨噬细胞，可显著增强LPS诱导的Raw264.7细胞中白细胞介素-12（IL-12）的表达。此外，用纯化的PAMM蛋白孵育Raw264.7细胞也有类似的抗炎作用。此外，在Raw264.7细胞中强制表达PAMM导致LPS诱导的ERK1/2、p38和c-Jun氨基末端激酶（JNK）磷酸化减少，这表明PAMM可能通过抑制丝裂原活化蛋白激酶（MAPK）信号通路发挥抗炎功能。PAMM的CXXC基序中抑制其抗氧化还原活性的突变仍然能够抑制LPS刺激的巨噬细胞中炎性细胞因子的产生，这表明PAMM的抗炎特性可能与其抗氧化特性无关。最后，PAMM在白色（WAT）和棕色脂肪组织（BAT）中均高表达，且在肥胖状态下进一步增加。我们的结果表明，脂肪细胞来源的PAMM可能通过抑制MAPK信号通路来抑制巨噬细胞活化。
