The value of cytokine levels in triage and risk prediction for women with persistent high-risk human papilloma virus infection of the cervix

Abstract

Background Cervical cancer is a common cancer among women worldwide and is closely related to high-risk human papillomavirus infection (HR-HPV). The immune microenvironment is thought to play an essential role in viral infection and cancer development; however, this relationship remains controversial. Cytokines are an important part of the immune system. Therefore, in this study, we explored changes in cervical cytokine levels of women with persistent HR-HPV infection and determined the value of cytokine detection in assessing cervical lesions. Methods We enrolled 146 patients; 117 had long-term high-risk (HR) HPV infection (> 6 months), and 29 were HPV-negative with previous HR-HPV infection. According to histopathological examination, 43 patients were diagnosed with cervicitis; 35, with low-grade squamous intraepithelial lesions (LSILs); and 39, with high-grade squamous intraepithelial lesions (HSILs). Cytokine levels in vaginal fluid were examined using cytometric bead array, and the values of interleukin (IL)-6 and IL-2 levels were converted to a cytokine score. The performance of the cytokine score for diagnosis and risk assessment was compared with that of ThinPrep cytology tests (TCTs). Results Disease severity was positively associated with IL-6 levels and inversely related to IL-2 levels. The area under the curve (AUC) was higher for the cytokine score including IL-6 and IL-2 than for TCTs for HSILs. Comparisons of the sensitivity, specificity, Youden index, and positive and negative predictive values for HSILs demonstrated that the cytokine score was better than TCT. HPV-positive patients with high cytokine scores showed increased risk of developing HSIL within 3 years. The hazard ratio for the cytokine score was 3.12; thus, the risk of developing HSIL was related to the cytokine score. Conclusions The cytokine score increased with the severity of cervical lesions and could distinguish more patients from HPV-positive women and predict the risk of disease progression.

Downregulation of IL-2 and IL-23 in Cervical Biopsies of Cervical Intraepithelial Lesions: A Cross-Sectional Study

“…In contrast, we found that IL-2 levels were significantly decreased in HSIL and LSIL samples compared to NSIL samples. This result agrees with a recent study showing that cervical disease severity was inversely related to IL-2 levels [13]. Although involved in Th2 differentiation, IL-2 is also considered an important Th1 pro-inflammatory cytokine [29,33].…”

“…In this study, we compared the cytokine profiles of cervical biopsies with histopathological diagnoses, using a panel that included key cytokines of each type of immune response: Th1 (IL-12 and IFN-γ), Th2 (IL-2 and IL-4), Treg (IL-10), and Th17 (IL-23 and IL-17) [13][14][15][16][17]. IL-2 and IL-23 were downregulated in HPV lesions, but the levels of the other cytokines displayed no significant association with lesion diagnosis.…”

“…Most studies on local immune response to HPV collect cervical mucus for cytokine measurements using either an endocervical brush or a cervicovaginal lavage [8][9][10][11][12][13][14][15][16], which essentially measures the spillover from cells located at the surface epithelium into the luminal fluid [17]. However, cells in other locations also release many cytokines involved in the immune response to infection.…”

Severe Inflammation Indicates High Risk of HSIL: from a Cross-Sectional Study

“…It can activate healing process and eliminate the injurious stimuli, which is considered as a mechanism of innate immunity [54]. Inflammation caused by genital infection can produce nonspecific protective antimicrobial oxidants which can also contribute to oxidative damage to host DNA, resulting in cancer [55].Inflammation related factors, like IL6, is an important factor promoting the progression of the disease and the development of tumors [56]. Many studies supported that inflammation is possibly a risk factor for carcinogenesis [15].Our study clearly showed a positive relationship between inflammation and HSIL, and 56.2% of HISL patients had CIN3.…”

Perfil intralesional de citocinas em lesões intraepiteliais de baixo e alto grau do colo uterino

“…A maioria dos estudos que avaliou a imunidade no colo uterino em mulheres com lesões intraepiteliais cervicais induzidas pelo HPV realizou a quantificação de citocinas no muco cervical ou lavado cervicovaginal (CASTLE et al, 2002;MARKS et al, 2011;TELESHEVA et al, 2012;SCOTT et al, 2013;EKALAKSANANAN et al, 2014;IWATA et al, 2015;DANIILIDIS et al, 2016;LI et al, 2019;OTANI et al, 2019). No entanto, muitas citocinas são expressas a partir de células específicas que não estão localizadas na superfície do epitélio e a avaliação da secreção cervicovaginal estaria medindo apenas o transbordamento destas substâncias para o lúmen vaginal.…”