α-MSH and its receptors in regulation of tumor necrosis factor-α production by human monocyte macrophages
α-MSH and its receptors in regulation of tumor necrosis factor-α production by human monocyte macrophages
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DOI：
10.1152/ajpregu.1999.276.5.r1289
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发表时间：
1999-05-01
影响因子：
2.8
通讯作者：
Lipton, JM
中科院分区：
文献类型：
--
作者：
Taherzadeh, S;Sharma, S;Lipton, JM
巨噬细胞含有基于黑皮质素 [ACTH 和 α-黑素细胞刺激激素 (α-MSH)] 肽的自分泌回路的假设对于神经免疫调节研究和炎症治疗具有重大意义。为了检验这一假设，在存在和不存在 α-MSH 的情况下，用脂多糖 (LPS) 刺激 THP-1 人单核细胞/巨噬细胞系的细胞。炎症细胞因子肿瘤坏死因子 (TNF)-α 受到抑制，与 α-MSH 浓度相关。使用含有 ol-MSH 氨基酸序列并作用于黑皮质素受体的 ACTH 肽观察到对 TNF-α 的类似抑制作用。核酸酶保护测定表明，THP-1 细胞中表达人黑皮质素-1 受体亚型 (hMC-1R)； RT-PCR 产物的 Southern 印迹显示还存在其他亚型 hMC-3R 和 hMC-5R。将静息巨噬细胞与 hMC-1R 抗体一起孵育可增加 TNF-α 浓度；该抗体还显着降低了 α-MSH 对经 LPS 处理的巨噬细胞中 TNF-α 的抑制作用。已知细胞在静止时产生 α-MSH 并在受到攻击时增加肽的分泌，这些结果与基于黑皮质素肽及其受体的内源性调节回路一致。在以骨髓单核细胞为主的炎症性疾病中，针对这种神经免疫调节回路应该是有益的。
The hypothesis that macrophages contain an autocrine circuit based on melanocortin [ACTH and alpha-melanocyte-stimulating hormone (alpha-MSH)] peptides has major implications for neuroimmunomodulation research and inflammation therapy. To test this hypothesis, cells of the THP-1 human monocyte/macrophage line were stimulated with lipopolysaccharide (LPS) in the presence and absence of alpha-MSH. The inflammatory cytokine tumor necrosis factor (TNF)-alpha was inhibited in relation to alpha-MSH concentration. Similar inhibitory effects on TNF-alpha were observed with ACTH peptides that contain the ol-MSH amino acid sequence and act on melanocortin receptors. Nuclease protection assays indicated that expression of the human melanocortin-1 receptor subtype (hMC-1R) occurs in THP-1 cells; Southern blots of RT-PCR product revealed that additional subtypes, hMC-3R and hMC-5R, also occur. Incubation of resting macrophages with antibody to hMC-1R increased TNF-alpha concentration; the antibody also markedly reduced the inhibitory influence of alpha-MSH on TNF-alpha in macrophages treated with LPS. These results in cells known to produce alpha-MSH at rest and to increase secretion of the peptide when challenged are consistent with an endogenous regulatory circuit based on melanocortin peptides and their receptors. Targeting of this neuroimmunomodulatory circuit in inflammatory diseases in which myelomonocytic cells are prominent should be beneficial.