Immunosuppressive cytokine Interleukin-10 (IL-10) is up-regulated in high-grade CIN but not associated with high-risk human papillomavirus (HPV) at baseline, outcomes of HR-HPV infections or incident CIN in the LAMS cohort

Abstract

Bypassing the local immunological defense reactions in the cervix is one of the prerequisites for human papillomaviruses (HPV) infections to progress to intraepithelial neoplasia (CIN). The role of potent immunosuppressive cytokines, e.g., interleukin-10 (IL-10), depressing these local virus-specific immunological responses is incompletely studied. To assess, whether IL-10 expression in cervical HPV lesions has any implications in the outcome of HPV infections or disease progression to CIN. Baseline cervical biopsies from 225 women of the LAMS study sub-cohort were analyzed for IL-10 expression using immunohistochemistry, to assess its associations with CIN grade, and high-risk HPV (HR-HPV) at baseline, as well as in predicting outcomes of HR-HPV infections, and development of incident CIN1+ and CIN2+ in this longitudinal setting. Expression of IL-10 in cervical lesions was up-regulated most often in high-grade CIN, and IL-10 over-expression retained its value as independent predictor of CIN2+ (odds ratio (OR) = 4.92) and CIN3+ (OR = 7.51) also in multivariate model, including HR-HPV and several known covariates of IL-10 expression. Up-regulation was not related to HR-HPV detection, and showed no relationship to HR-HPV viral loads. Using longitudinal predictive indicators (SE, SP, PPV, NPV), IL-10 expression was of no value in predicting (1) the outcomes of HR-HPV infections, or (2) the surrogate endpoints (incident CIN1+, CIN2+) of progressive disease. IL-10 over-expression (along with HR-HPV) was one of the independent covariates of CIN2/3. This immunosuppressive cytokine might play an important role in creating a microenvironment that favors progressive cervical disease and immune evasion by HR-HPV.

Differential Impact of IL-10 Expression on Survival and Relapse between HPV16-Positive and -Negative Oral Squamous Cell Carcinomas

“…A link has been shown between IL-10 expression and HPV-infected CIN progression [35]. Therefore, we expected to find differential IL-10 mRNA expression levels between HPV-positive and -negative OSCC.…”

“…Therefore, IL-10 has been documented to determine in vivo virus clearance or persistent infection. Previously, IL-10 expression levels were reported as significantly higher in an HPV16-infected high grade of cervical intraepithelial neoplasia (CIN) II and III when compared to normal cervical epithelium and CIN I [33]–[35]. This suggests that IL-10 production may play a role in the progression of HPV-associated cervical precancer [34].…”

The paradox of IL-10-mediated modulation in cervical cancer

“…Expression of IL-10 in cervical lesions was most commonly upregulated in high-grade CIN. This immunosuppressive cytokine may play an important role in creating a microenvironment that favors progressive cervical disease and immune evasion by high-risk HPV (31) and may also explain the immunosuppressive state of cervical cancer patients (32). Women who are genetically programmed to produce high or moderate levels of IL-10 are more likely to develop cancer of the uterine cervix, compared to individuals genetically predisposed to low IL-10 production, suggesting that the genetically acquired ability to produce higher levels of IL-10 may be a significant factor in the development of cervical cancer (17).…”

Slumbering mucosal immune response in the cervix of human papillomavirus DNA-positive and -negative women

“…In women with HPV16-positive CIN, El-Sherif et al observed decreased levels of IFNÁ and TGFß mRNA and increases of IL-10 compared to healthy HPV-negative controls (36,37). Others recently found that elevations in IFNÁ and IL-10 were associated with decreased odds of having CIN 2 or 3 (38,39). Using immunohistochemistry, Behbahani et al located more IL-2 and IL-4 expressing cells as signs of immune activation in HPV-positive women compared to negative controls (22).…”