Diversity of interferon γ and granulocyte-macrophage colony-stimulating factor in restoring immune dysfunction of dendritic cells and macrophages during polymicrobial sepsis
Diversity of interferon γ and granulocyte-macrophage colony-stimulating factor in restoring immune dysfunction of dendritic cells and macrophages during polymicrobial sepsis
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DOI：
10.2119/2007-00120.flohe
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发表时间：
2008-05-01
影响因子：
5.7
通讯作者：
Schade, F. Ulrich
中科院分区：
文献类型：
--
作者：
Flohe, Stefanie B.;Agrawal, Hemant;Schade, F. Ulrich
多菌败血症时免疫抑制的发生与树突状细胞(DC)不能促进辅助性T细胞(Th)向保护性Th I型极化有关，本研究的目的是测试潜在的免疫调节方法以恢复脾DC分泌IL 12的能力，IL 12是Th I细胞极化中的关键细胞因子。盲肠结扎和穿孔(CLP)诱导小鼠多菌败血症，在CLP或假手术后不同时间点分离脾DC，并在有或没有中和抗IL-10抗体、小鼠干扰素(IFN)、伽马的情况下用细菌成分刺激和/或粒细胞巨噬细胞集落刺激因子(GM-CSF)。脓毒症小鼠来源的DC对细菌刺激的反应显示出释放促炎和促进Th1的细胞因子肿瘤坏死因子a、干扰素-γ和IL-12的能力受损，但分泌IL-10。内源性IL-10不是IL-12分泌受损的原因。至CLP后6h，联合干扰素-γ和GM-CSF的脓毒症小鼠DC可增加IL-12的分泌。随后，脓毒症小鼠DC对干扰素-γ和GM-CSF的反应是共刺激分子CD86表达增加，而IL-12的分泌不再增强。相比之下，脓毒症晚期小鼠的脾巨噬细胞对GM-CSF的反应是细胞因子释放增加。因此，干扰素-γ/粒-巨噬细胞集落刺激因子治疗脓毒症可能足以恢复巨噬细胞的活性，但不能恢复足以产生保护性Th1样免疫反应的DC功能。
The development of immunosuppression during polymicrobial sepsis is associated with the failure of dendritic cells (DC) to promote the polarization of T helper (Th) cells toward a protective Th I type, The aim of the study was to test potential Immunomodulatory approaches to restore the capacity of splenic DC to secrete interleukin (IL) 12 that represents the key cytokine in Th I cell polarization, Murine polymicrobial sepsis was induced by cecal ligation and puncture (CLP), Splenic DC were isolated at different time points after CLP or sham operation, and stimulated with bacterial components in the presence or absence of neutralizing anti-IL-10 antibodies, murine interferon (IFN)gamma, and/or granulocyte macrophage colony-stimulating factor (GM-CSF). DC from septic mice showed an impaired capacity to release the pro-inflammatory and Th1-promoting cytokines tumor necrosis factor a, IFN-gamma, and IL-12 in response to bacterial stimuli, but secreted IL-10. Endogenous IL-10 was not responsible for the impaired IL-12 secretion. Up to 6 h after CLP, the combined treatment of DC from septic mice with IFN-gamma and GM-CSF increased the secretion of IL-12. Later, DC from septic mice responded to IFN-gamma and GM-CSF with increased expression of the co-stimulatory molecule CD86, while IL-12 secretion was no more enhanced. In contrast, splenic macrophages from septic mice during late sepsis responded to GM-CSF with increased cytokine release. Thus, therapy of sepsis with IFN-gamma/GM-CSF might be sufficient to restore the activity of macrophages, but fails to restore DC function adequate for the development of a protective Th1-like immune response.