HIV-1感染通过诱导IL-6促进可溶性PD-1的表达
|
摘要
目的探索艾滋病病毒1型(HIV-1)感染者血浆中可溶性程序性细胞死亡受体1(sPD-1)表达水平增高的原因。方法采用流式微球阵列多重蛋白定量检测技术,检测HIV-1感染者(HIV组)和健康人(HD组)外周血13种炎症性细胞因子的含量,分析其与血浆sPD-1水平的相关性;体外分析相关细胞因子对外周血单个核细胞sPD-1表达水平的影响。结果 HIV组(n=31)血浆sPD-1蛋白含量平均(295.21±167.7) pg/mL,显著高于HD组(n=30)的(104.69±72.04)pg/mL(P<0.000 1);此外,HIV组血浆γ干扰素(IFN-γ)、α肿瘤坏死因子(TNF-α)、人单核细胞趋化蛋白-1(MCP-1)、白细胞介素6(IL-6)、IL-10、IL-12、IL-33等7种炎症性细胞因子含量显著高于HD组,且MCP-1(P<0.000 1,r=0.581 2)和IL-6(P=0.006 1,r=0.350 1)含量与血清sPD-1水平呈正相关,而重组人IL-6可显著增强健康人外周血单个核细胞表达sPD-1(P=0.000 3)。结论 HIV-1可能通过诱导炎症性细胞因子IL-6的分泌,进而促进sPD-1的表达。
Objective To explore the causes of increased expression of soluble programmed cell death receptor 1(sPD-1) in plasma of HIV-1 infected patients. Methods The level of 13 inflammatory cytokines in plasma of HIV-1 infected patients(HIV group) and healthy donors(HD group) was detected by cytometric bead array(CBA) multi-protein quantitative detection technique. Then the correlation was analyzed between the contents of inflammatory cytokines and plasma sPD-1 level. Furthermore, the effects of related cytokines on the expression of sPD-1 in peripheral blood mononuclear cells were analyzed in vitro. Results The level of sPD-1 in HIV group(n=31) was 295.21±167.7 pg/mL, which was significantly higher(P<0.000 1) than that in HD group(n=30,104.7±72.04 pg/mL). In addition, plasma level of INF-γ, TNF-α, MCP-1, IL-6, IL-10, IL-12, IL-33 in HIV group was significantly higher than that in HD group. Furthermore, the plasma level of MCP-1(P<0.000 1,r=0.581 2) and IL-6(P=0.006 1,r=0.350 1) was positively correlated with sPD-1, and the recombinant human IL-6 could significantly enhanced sPD-1 expression in the peripheral blood mono-nuclear cells of HD group(P=0.000 3). Conclusion HIV-1 may promote the expression of sPD-1 by inducing the secretion of inflammatory cytokine IL-6.
Objective To explore the causes of increased expression of soluble programmed cell death receptor 1(sPD-1) in plasma of HIV-1 infected patients. Methods The level of 13 inflammatory cytokines in plasma of HIV-1 infected patients(HIV group) and healthy donors(HD group) was detected by cytometric bead array(CBA) multi-protein quantitative detection technique. Then the correlation was analyzed between the contents of inflammatory cytokines and plasma sPD-1 level. Furthermore, the effects of related cytokines on the expression of sPD-1 in peripheral blood mononuclear cells were analyzed in vitro. Results The level of sPD-1 in HIV group(n=31) was 295.21±167.7 pg/mL, which was significantly higher(P<0.000 1) than that in HD group(n=30,104.7±72.04 pg/mL). In addition, plasma level of INF-γ, TNF-α, MCP-1, IL-6, IL-10, IL-12, IL-33 in HIV group was significantly higher than that in HD group. Furthermore, the plasma level of MCP-1(P<0.000 1,r=0.581 2) and IL-6(P=0.006 1,r=0.350 1) was positively correlated with sPD-1, and the recombinant human IL-6 could significantly enhanced sPD-1 expression in the peripheral blood mono-nuclear cells of HD group(P=0.000 3). Conclusion HIV-1 may promote the expression of sPD-1 by inducing the secretion of inflammatory cytokine IL-6.
引文
[1] Roan NR. Resident T cells stand up to HIV[J]. Sci Immunol, 2018, 3(24): eaat6121.
[2] Mattevi VS, Tagliari CF. Pharmacogenetic considerations in the treatment of HIV[J]. Pharmacogenomics, 2017, 18(1):85-98.
[3] Pitman MC, Lau JSY, McMahon JH, et al. Barriers and strategies to achieve a cure for HIV[J]. Lancet HIV, 2018, 5(6):e317-e328.
[4] Day CL, Kaufmann DE, Kiepiela P, et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression[J]. Nature, 2006, 443(7109): 350-354.
[5] Trautmann L, Janbazian L, Chomont N, et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction[J]. Nat, Med, 2006, 12(10): 1198-1202.
[6] 肖金凤, 徐六妹, 李莎茜,等. HIV-1感染者血浆可溶性PD-1的含量及其临床意义[J]. 中国艾滋病性病, 2016, 22(11):853-855.
[7] Grabmeier-Pfistershammer K, Stecher C, Zettl M, et al. Antibodies targeting BTLA or TIM-3 enhance HIV-1 specific T cell responses in combination with PD-1 blockade[J]. Clin Immunol, 2017 (183):167-173.
[8] Walshaw RC, Honeychurch J, Illidge TM, et al. The anti-PD-1 era-an opportunity to enhance radiotherapy for patients with bladder cancer[J]. Nat Rev Urol, 2018, 15(4):251-259.
[9] Zhang J, Zhang Z, Wang X, et al. PD-1 up-regulation is correlated with HIV-specific memory CD8+T-cell exhaustion in typical progressors but not in long-term nonprogressors[J]. Blood, 2007, 109(11): 4671-4678.
[10] Palmer BE, Neff CP, Lecureux J, et al. In vivo blockade of the PD-1 receptor suppresses HIV-1 viral loads and improves CD4+ T cell levels in humanized mice[J]. J Immunol, 2013, 190(1):211-219.
[11] Liu C, Jiang J, Gao L, et al. Soluble PD-1 aggravates progression of collagen-induced arthritis through Th1 and Th17 pathways[J]. Arthritis research & therapy, 2015(17): 340.
[12] Bandera A, Colella E, Rizzardini G, et al. Strategies to limit immune-activation in HIV patients[J]. Expert Rev Anti Infect Ther, 2017, 15(1):43-54.
[13] Nielsen C, Ohm-Laursen L, Barington T, et al. Alternative splice variants of the human PD-1 gene[J]. Cell Immunol, 2005, 235(2): 109-116.
[2] Mattevi VS, Tagliari CF. Pharmacogenetic considerations in the treatment of HIV[J]. Pharmacogenomics, 2017, 18(1):85-98.
[3] Pitman MC, Lau JSY, McMahon JH, et al. Barriers and strategies to achieve a cure for HIV[J]. Lancet HIV, 2018, 5(6):e317-e328.
[4] Day CL, Kaufmann DE, Kiepiela P, et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression[J]. Nature, 2006, 443(7109): 350-354.
[5] Trautmann L, Janbazian L, Chomont N, et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction[J]. Nat, Med, 2006, 12(10): 1198-1202.
[6] 肖金凤, 徐六妹, 李莎茜,等. HIV-1感染者血浆可溶性PD-1的含量及其临床意义[J]. 中国艾滋病性病, 2016, 22(11):853-855.
[7] Grabmeier-Pfistershammer K, Stecher C, Zettl M, et al. Antibodies targeting BTLA or TIM-3 enhance HIV-1 specific T cell responses in combination with PD-1 blockade[J]. Clin Immunol, 2017 (183):167-173.
[8] Walshaw RC, Honeychurch J, Illidge TM, et al. The anti-PD-1 era-an opportunity to enhance radiotherapy for patients with bladder cancer[J]. Nat Rev Urol, 2018, 15(4):251-259.
[9] Zhang J, Zhang Z, Wang X, et al. PD-1 up-regulation is correlated with HIV-specific memory CD8+T-cell exhaustion in typical progressors but not in long-term nonprogressors[J]. Blood, 2007, 109(11): 4671-4678.
[10] Palmer BE, Neff CP, Lecureux J, et al. In vivo blockade of the PD-1 receptor suppresses HIV-1 viral loads and improves CD4+ T cell levels in humanized mice[J]. J Immunol, 2013, 190(1):211-219.
[11] Liu C, Jiang J, Gao L, et al. Soluble PD-1 aggravates progression of collagen-induced arthritis through Th1 and Th17 pathways[J]. Arthritis research & therapy, 2015(17): 340.
[12] Bandera A, Colella E, Rizzardini G, et al. Strategies to limit immune-activation in HIV patients[J]. Expert Rev Anti Infect Ther, 2017, 15(1):43-54.
[13] Nielsen C, Ohm-Laursen L, Barington T, et al. Alternative splice variants of the human PD-1 gene[J]. Cell Immunol, 2005, 235(2): 109-116.