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白细胞介素12增强HIV血清阳性个体外周血单个核细胞的T细胞增殖与白细胞介素12受体β2上调有关。

Interleukin 12-augmented T cell proliferation of peripheral blood mononuclear cells from HIV-seropositive individuals is associated with interleukin 12 receptor beta 2 upregulation.

作者信息

Jones Matthew L, Young Judy M, Huang Qi Rong, Puls Rebekah L, Webber Carolyn A, Benson Elizabeth M

机构信息

Department of Immunopathology, Institute of Clinical Pathology and Medical Research, Westmead Hospital, Wentworthville, NSW 2145, Australia.

出版信息

AIDS Res Hum Retroviruses. 2003 Apr;19(4):283-92. doi: 10.1089/088922203764969483.

Abstract

Interleukin 12 (IL-12) production is believed to be impaired in individuals with HIV infection and this impairment manifests early in disease, when the CD4(+) cell counts are within normal values. The reduced antigen-specific and mitogen-stimulated T cell-proliferative responses that occur in HIV infection can be corrected by the addition of recombinant human interleukin 12 (rhIL-12). As the IL-12 receptor (IL-12R) is central to the IL-12 signaling pathway, we examined whether the augmentation of antigen-specific proliferation of HIV(+) peripheral blood mononuclear cells (PBMCs) related to altered IL-12R expression. rhIL-12 augmented antigen-specific proliferation of HIV(+) PBMCs but not of HIV(-) PBMCs. Examination of resting PBMCs from HIV(+) and HIV(-) donors showed that neither of these populations expressed IL-12R beta 1 or IL-12R beta 2 chains on their cell surface as detected by flow cytometry. However, examination of mRNA showed that both IL-12R beta 1 and IL-12R beta 2 mRNAs were markedly reduced in HIV(+) PBMCs when compared with HIV(-) PBMCs. After mitogen activation there was an increase in IL-12R beta 1 expression on the cell surface of HIV(+) and HIV(-) PBMCs and this level was not altered by coculture with rhIL-12 or interferon gamma (IFN-gamma). However, coculture of phytohemagglutinin (PHA)-activated HIV(+) or HIV(-) PBMCs with rhIL-12 (but not IFN-gamma) increased IL-12R beta 2 expression on the cell surface of both populations. Examination at the message level showed a correction of IL-12R beta 1 to normal levels with activation that was further enhanced by rhIL-12 coculture for both the HIV(+) and HIV(-) PBMCs. However, although the level of IL-12R beta 2 for the HIV(+) PBMCs was normalized by PHA, rhIL-12 caused a further augmentation. This information provides a strong link between IL-12R upregulation, and the significant improvement in antigen-specific HIV-proliferative responses seen with the addition of rhIL-12. It also reveals that the dysfunction in IL-12R expression seen in cells from HIV(+) patients occurs at the transcriptional level. In addition, we provide further evidence that IL-12R beta 1 and IL-12R beta 2 regulation in human PBMCs is independent of IFN-gamma.

摘要

据信,HIV感染者体内白细胞介素12(IL-12)的产生受损,且这种损害在疾病早期就会出现,此时CD4(+)细胞计数仍在正常范围内。HIV感染时出现的抗原特异性和丝裂原刺激的T细胞增殖反应降低,可通过添加重组人白细胞介素12(rhIL-12)得到纠正。由于IL-12受体(IL-12R)是IL-12信号通路的核心,我们研究了HIV(+)外周血单个核细胞(PBMC)抗原特异性增殖的增强是否与IL-12R表达改变有关。rhIL-12增强了HIV(+) PBMC的抗原特异性增殖,但未增强HIV(-) PBMC的增殖。对HIV(+)和HIV(-)供体的静息PBMC进行检测,通过流式细胞术检测发现,这两种细胞群体在细胞表面均未表达IL-12Rβ1或IL-12Rβ2链。然而,对mRNA的检测显示,与HIV(-) PBMC相比,HIV(+) PBMC中IL-12Rβ1和IL-12Rβ2 mRNA均显著减少。丝裂原激活后,HIV(+)和HIV(-) PBMC细胞表面的IL-12Rβ1表达增加,与rhIL-12或干扰素γ(IFN-γ)共培养后,该水平未发生改变。然而,将植物血凝素(PHA)激活的HIV(+)或HIV(-) PBMC与rhIL-12(而非IFN-γ)共培养,可增加这两种细胞群体细胞表面的IL-12Rβ2表达。在mRNA水平检测发现,激活后HIV(+)和HIV(-) PBMC的IL-12Rβ1水平恢复正常,rhIL-12共培养可进一步增强。然而,尽管HIV(+) PBMC的IL-12Rβ2水平经PHA处理后恢复正常,但rhIL-12可使其进一步升高。这些信息表明IL-12R上调与添加rhIL-12后抗原特异性HIV增殖反应的显著改善之间存在紧密联系。这也揭示了HIV(+)患者细胞中IL-12R表达的功能障碍发生在转录水平。此外,我们进一步证明,人PBMC中IL-12Rβ1和IL-12Rβ2的调节独立于IFN-γ。

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