RESUMO
TNF-α is involved in HPV infection control by triggering cell signaling through binding in specific receptors TNFR1 and TNFR2. Genetic polymorphisms in these receptors may influence TNF-α signaling. Herein, we investigated TNFR1 rs767455 and rs2234649 single nucleotide polymorphisms, and TNFR1 protein expression in cervical squamous intraepithelial lesions (SIL) to identify their role in cervical pre-malignant development. SIL patients (n = 179) and healthy volunteers (n = 227) were enrolled for TNFR1 genotyping analysis by PCR-RFLP in blood samples and TNFR1 protein expression in cervical tissue by immunohistochemistry. No statistical differences regard genotypes and allelic frequencies for both polymorphisms were observed. Cervical TNFR1-expressing cells were rare in epithelium and basal layer regardless the groups. However, a progressive increase in infiltrating cells was observed in the stromal area, mainly in high SIL (HSIL) group compared to low SIL (LSIL, p < 0.001) and control (p < 0.001) groups. TNFR1-expressing cells frequency was higher in TNFR1 rs767455AG/GG (p < 0.001), and in rs2234649AA (p < 0.001) genotypes carries in HSIL subgroup. These data indicated that TNFR1-expression is abrogated in cervical epithelium, where HPV-induced pre-malignant lesion occurs, increasing its frequency in inflammatory cells in stroma, and is genetically controlled by TNFR1 rs767455AG/GG and rs234649AA genotypes. These biomarkers may be useful to identify cervical precancerous lesions progression.
RESUMO
Cell-mediated cytotoxicity plays an important role in the regulation to HPV-associated cervical intraepithelial neoplasia. HIV co-infection is related to poorer prognosis and more rapid clinical progression to cancer. We evaluated the presence of cervical inflammatory cells, apoptotic (Bax, Bcl-2, FasL, NOS2, perforin) markers and the degranulating expressing cell marker (CD107a) in low and high squamous intraepithelial lesions (LSIL and HSIL, respectively) from HIV-negative and -positive women. Higher percentage of cervical CD4(+), CD8(+) T cells and macrophage were observed in LSIL and HSIL groups when compared with control, especially in epithelium and basal layer of epithelium. However, progression from LSIL to HSIL did not change the frequency of inflammatory cells. HIV-infection lead to a reduction on cervical CD4(+) T cell infiltration and an increased CD8(+) T cell distribution in LSIL groups. A balance between pro- and anti-apoptotic protein expressions was verified. Bax-expressing cells were present in all groups and were rarely expressed in keratinocytes in the epithelium in LSIL and control groups, but notably decreased in HSIL group. However, its frequency was enhanced in the basal layer of the epithelium meanly in LSIL group. Bcl2-expressing cells in the epithelium and the stroma were enhanced in HSIL group when compared with LSIL group. HIV-infection did not interfere in both expressions NOS2 expression was located on keratinocytes in both LSIL and HSIL groups when compared with control group. There were few FasL cervical expressing cells in all groups. Indeed, perforin was identified in few cervical cells. However, CD107a, a surface marker for cellular degranulation was significantly higher in epithelium, basal layer of epithelium and stroma in LSIL and HSIL, respectively, when compared with control group. These results support that HIV infection may induce reduction on inflammatory cervical cell degranulation corroborating to carcinogenesis process. This is the first description on the role of HIV in downregulation of perforin degranulation in the cervical lesions and it might be related to carcinogenesis.