Cytokine expression in squamous intraepithelial lesions of the uterine cervix: implications for the generation of local immunosuppression

Abstract

We have addressed the notion that the progression of cancer of the uterine cervix is associated with a preferential constraint on the development of a type 1 cellular mediated response, which is necessary to efficiently eliminate (pre)neoplastic cells. Based on the importance of cytokines in the regulation of an appropriate immune response, we have evaluated the expression of IL-12p40, IL-10 and transforming growth factor-beta 1 (TGF-beta1). Using reverse transcriptase-polymerase chain reaction (RT-PCR), the expression of these three cytokines was evaluated in both low-grade (LG) and high-grade (HG) cervical squamous intraepithelial lesions (SIL) and in normal exocervix and transformation zone biopsies. Our results show that the average level of IL-12 increases within both the LG and HG SIL, compared with both control groups. Interestingly, the percentage of HG SIL expressing IL-12p40 was lower compared with LG SIL. In contrast, the expression of IL-10 increased in parallel with the severity of the lesion to a maximal level in HG SIL. Using immunohistochemistry, we ascertained the presence of IL-12 protein in SIL and IL-10 protein in the transformation zone and SIL biopsies. Both IL-12- and IL-10-producing cells were localized in the stroma, not within the SIL. Furthermore, in this study we also observed that the region of the cervix the most sensitive to lesion development, the transformation zone, was associated with higher average levels of the immunosuppressive cytokines IL-10 and TGF-beta1.

Influence of the mucosal epithelium microenvironment on Langerhans cells: Implications for the development of squamous intraepithelial lesions of the cervix

“…Furthermore, we have shown that the development of SILs, although associated with a relative increase in immature LC, is deficient in their presentation of alloantigens to T cells (proliferation) compared to the TZ. In addition, as previously observed in situ, 6 we confirm that the micro environment of the TZ and SILs is more frequently associated with IL10 production. Moreover, a potential correlation was also observed between the differential frequency of expression of MIP3␣ and/or TNF␣ and the density of immature LC (CD1a/ LAG) in the exocervix, TZ and SILs.…”

“…[35][36][37] Consequently, the increased expression of IL10 within the microenvironment of the TZ and SILs in situ and the ability of TZ and SIL derived epithelial cells to induce IL10 in PBMC in vitro implicate this cytokine as a factor likely to influence the establishment and development of SILs. 6 Other factors and/or mechanisms besides IL10 may contribute to the reduced alloantigen presentation by SIL-derived LC, such as apoptosis, the aberrant activation/differentiation of LC in the presence of HPV or other factors including the overexpression of VEGF or IL6 observed in SILs. 4,38,39 Alternatively, HLA-DR ϩ keratinocytes that are frequently detected in SILs may interfere with LC function and induce T cell tolerance.…”

“…Nevertheless, we and others have suggested that other factors may contribute to the sensitivity of the TZ to SIL development. 6,17,18 For example, we have observed that the density of LC is significantly reduced and the immunosuppressive cytokine IL10 is more frequently expressed in the microenvironment of TZ in comparison to the exocervix. 5,6,17 To the contrary, other groups have reported that the density of LC in the TZ is equal to that of the exocervix.…”

“…6,17,18 For example, we have observed that the density of LC is significantly reduced and the immunosuppressive cytokine IL10 is more frequently expressed in the microenvironment of TZ in comparison to the exocervix. 5,6,17 To the contrary, other groups have reported that the density of LC in the TZ is equal to that of the exocervix. 19,20 As an approach to understanding the factors involved in the initiation and progression of SILs, we sought to use a variety of methods to assess the differential density and the antigen presenting function of LC derived from TZ and SILs.…”

Role of hormone cofactors in the human papillomavirus-induced carcinogenesis of the uterine cervix

“…Moreover, specific T cells cocultured with estradiol-pretreated mature DC in the presence of antigens exhibit a shift towards a production of type II cytokines such as IL4 and IL10 (Liu et al, 2002). Interestingly, a co-expression of IL10 and IL4 has been demonstrated in established (pre)neoplasic lesions of the cervix (Al Giannini et al, 1998) and suggests the presence of a type II cytokine pattern instead of a cell-mediated anti-tumor immunity. This inappropriate response against intracellular infectious agents, such as viruses or tumor cells may lead to the persistence of HPV by preventing infected cells from being eliminated by cytotoxic T lymphocytes.…”