Haga Takeshi, Efird Jimmy T, Tugizov Sharof, Palefsky Joel M
Division of Infection Control and Disease Prevention, Department of Veterinary Medical Science, University of Tokyo, Tokyo 113-8657, Japan; Department of Medicine, University of California, San Francisco, CA 94143, USA.
Center for Health Disparities and College of Nursing, East Carolina University, Greenville, NC 27858, USA; School of Medicine and Public Health, University of Newcastle, Newcastle, NSW 2308, Australia.
Papillomavirus Res. 2017 Jun;3:1-6. doi: 10.1016/j.pvr.2016.11.003. Epub 2016 Dec 1.
Compared with HIV-negative individuals, HIV-positive individuals have a higher prevalence of anogenital human papillomavirus (HPV) infection, the causative agent of anogenital cancer. TNF-alpha is a major proinflammatory cytokine. sTNFR2 is the soluble form of one of its receptors and is strongly expressed on stimulated lymphocytes. To further understand the role of TNF-alpha, sTNFR2 and other cytokines in the pathogenesis in HPV-related neoplasia, the profiles of serum cytokines in high-risk patients were analyzed for association with anal lesion status. Patients were categorized into 4 groups based on HIV status (HIV-negative vs. HIV-positive with a CD4+ level <200/uL) and anal lesion status [no lesion, low-grade anal squamous intraepithelial lesion (LSIL) vs. high-grade squamous intraepithelial lesion (HSIL)] based on high resolution anoscopy-guided biopsy. Following adjustment for multiplicity, HIV-negative men with HSIL had lower levels of sTNFR2 than HIV-positive men with low CD4 level and HSIL (p=0.02). HIV-positive men with HSIL had higher levels of TNF-alpha than HIV-negative men with HSIL (p<0.001), as well as HIV-positive men with no lesion or LSIL (p=0.03). The levels of other factors, including IL-1beta, IL-2, IL-4, IL-8, IFN-gamma, GM-CSF, sTNFR1 and DR5, were not significantly different between groups. Although the sample size was small, these results suggest that systemic activation of TNF-alpha/sTNFR2 in HIV-positive patients with a low CD4 level may promote the development of HSIL and possibly anal cancer.
与HIV阴性个体相比,HIV阳性个体的肛门生殖器人乳头瘤病毒(HPV)感染患病率更高,而HPV是肛门生殖器癌的病原体。肿瘤坏死因子-α(TNF-α)是一种主要的促炎细胞因子。可溶性肿瘤坏死因子受体2(sTNFR2)是其一种受体的可溶性形式,在受刺激的淋巴细胞上强烈表达。为了进一步了解TNF-α、sTNFR2和其他细胞因子在HPV相关肿瘤发病机制中的作用,分析了高危患者血清细胞因子谱与肛门病变状态的相关性。根据HIV状态(HIV阴性与CD4+水平<200/μL的HIV阳性)和基于高分辨率肛门镜引导活检的肛门病变状态[无病变、低度肛门鳞状上皮内病变(LSIL)与高度鳞状上皮内病变(HSIL)],将患者分为4组。在对多重性进行校正后,患有HSIL的HIV阴性男性的sTNFR2水平低于CD4水平低且患有HSIL的HIV阳性男性(p=0.02)。患有HSIL的HIV阳性男性的TNF-α水平高于患有HSIL的HIV阴性男性(p<0.001),也高于无病变或患有LSIL的HIV阳性男性(p=0.03)。包括白细胞介素-1β(IL-1β)、白细胞介素-2(IL-2)、白细胞介素-4(IL-4)、白细胞介素-8(IL-8)、干扰素-γ(IFN-γ)、粒细胞-巨噬细胞集落刺激因子(GM-CSF)、可溶性肿瘤坏死因子受体1(sTNFR1)和死亡受体5(DR5)在内的其他因子水平在各组之间无显著差异。尽管样本量较小,但这些结果表明,CD4水平低的HIV阳性患者中TNF-α/sTNFR2的全身激活可能促进HSIL的发展,并可能促进肛门癌的发生。