Increased secretion patterns of interleukin-10 and tumor necrosis factor-alpha in cervical squamous intraepithelial lesions

Cytokines are released in response to infection of the uterine cervix by high-risk HPV. By using enzyme-linked immunosorbent assay, we measured the levels of tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (INF-gamma), interleukin-6 (IL-6), and interleukin-10 (IL-10) in the cervical secretions of 120 cytologically normal or equivocal and 91 abnormal Japanese women. HPV infection of the cervical cells was typed by the LCR-E7 PCR method. The HPV DNA-negative samples were classified as either normal or inflamed, and the HPV DNA-positive samples were classified as HPV positive(+) n-ormal and as low- or high-grade squamous intraepithelial lesions (SILs). Compared with the normal cervices, all of the cytokines tested were elevated in inflamed, HPV+ normal, low-grade SILs (LSIL), and high-grade SILs (HSIL). The level of IL-10 was statistically higher in LSIL, and the level of TNF-alpha was higher in HSIL, relative to the cytokine levels in the inflamed and HPV+ normal samples (P <0.05; Mann-Whitney test). Multivariate analyses confirmed that increased levels of IL-10 were associated with LSIL (relative risk RR]=3.9, 95% confidence interval CI]=1.7-8.8) and that increased levels of TNF-alpha (RR=4.6, 95% CI=1.4-15) and age older than 40 years (RR=8.5, 95% CI=1.3-56) were associated with HSIL. The levels of INF-gamma and TNF-alpha (Th1-cytokines) correlated negatively with those of IL-6 and IL-10 (Th2-cytokines) in HPV+ normal and LSIL subjects, whereas no such correlation was observed for HSIL. The up-regulated secretion of IL-10 may inhibit immune responses against HPV infection in early cervical lesions, whereas up-regulated TNF-alpha and uncoordinated cytokine secretion (elevated both Th1 and Th2 cytokines) may reflect impaired or invalid responses in advanced stage lesions. The detection of IL-10 and TNF-alpha in cervical secretions may be a useful indicator of local immune responses and of the stage of the cervical lesions induced by HPV infection.