Recombinant methionyl human leptin administration activates signal transducer and activator of transcription 3 signaling in peripheral blood mononuclear cells in vivo and regulates soluble tumor necrosis factor-α receptor levels in humans with relative leptin deficiency
Recombinant methionyl human leptin administration activates signal transducer and activator of transcription 3 signaling in peripheral blood mononuclear cells in vivo and regulates soluble tumor necrosis factor-α receptor levels in humans with relative leptin deficiency
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DOI：
10.1210/jc.2004-1823
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发表时间：
2005-03-01
影响因子：
5.8
通讯作者：
Mantzoros, CS
中科院分区：
文献类型：
--
作者：
Chan, JL;Moschos, SJ;Mantzoros, CS
动物和人类先天性瘦素完全缺乏的研究支持瘦素在调节免疫功能中的作用。获得性相对瘦素缺乏是否影响健康人的免疫学参数仍不清楚。因此，我们使用相对瘦素缺乏的实验模型和重组甲硫氨酰人瘦素本发明的目的是在人类中施用瘦素（r-metHuLeptin）以研究r-metHuLeptin是否会激活外周血单核细胞（PBMC）中的信号传导途径，以及获得性相对瘦素缺乏和/或将循环瘦素水平增加到生理范围是否会改变PBMC亚群和在T细胞中重要的细胞因子。辅助细胞和全身免疫反应。我们发现对健康人施用r-metHuLeptin在体内激活PBMC中的信号转导子和转录激活子-3信号传导。无论是短期的瘦素缺乏症，诱导的3天完全禁食，也没有生理r-metHuLeptin替代相同的时间内有一个主要的影响PBMC亚群或血清细胞因子在健康男性。相比之下，正常血清瘦素水平超过8周的瘦妇女与相对瘦素缺乏5.1 +/- 1.4年（平均+/- SE），由于慢性能量不足增加可溶性TNF α受体水平，表明激活的TNF α系统。这些研究结果表明，由于更长期的能量剥夺的相对瘦素缺乏与免疫参数的缺陷，可以纠正外源性r-metHuLeptin管理。需要进一步研究以评估获得性相对低瘦素血症和/或r-metHuLeptin给药对人类能量和瘦素缺乏状态相关免疫抑制的影响。
Studies of congenital complete leptin deficiency in animals and humans support a role for leptin in regulating immune function. Whether acquired relative leptin deficiency affects immunological parameters in healthy humans remains unknown. We thus used experimental models of relative leptin deficiency and recombinant methionyl human leptin (r-metHuLeptin) administration in humans to investigate whether r-metHuLeptin would activate signaling pathways in peripheral blood mononuclear cells (PBMCs) and whether acquired relative leptin deficiency and/or increasing circulating leptin levels into the physiologic range would change PBMC subpopulations and cytokines important in the T-helper cell and systemic immune responses. We found that r-metHuLeptin administration to healthy humans activates signal transducer and activator of transcription-3 signaling in PBMCs in vivo. Neither short-term leptin deficiency, induced by 3-d complete fasting, nor physiologic r-metHuLeptin replacement for the same period of time had a major effect on PBMC subpopulations or serum cytokines in healthy men. In contrast, normalizing serum leptin levels over 8 wk in lean women with relative leptin deficiency for 5.1 +/- 1.4 yr ( mean +/- SE) due to chronic energy deficit increased soluble TNF alpha receptor levels, indicating activation of the TNF alpha system. These findings suggest that relative leptin deficiency due to more long-term energy deprivation is associated with defects in immunological parameters that may be corrected with exogenous r-metHuLeptin administration. Further studies are warranted to assess the implications of acquired relative hypoleptinemia and/or r-metHuLeptin administration on the immunosuppression associated with energy- and leptin-deficient states in humans.