Differences in cytokine mRNA profiles between premalignant and malignant lesions of the uterine cervix

Gruijl, Tanja D. de; Bontkes, Hetty J.; Muysenberg, Adrie J.C. van den; Oostveen, J. W. Van; Stukart, M. J.; Verheijen, René H.M.; Vange, N. van der; Snijders, Peter J.F.; Meijer, Chris J.L.M.; Walboomers, Jan M. M.; Rj, Scheper

doi:10.1016/s0959-8049(98)00371-2

Cited by 54 publications

(34 citation statements)

References 27 publications

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“…In cervical cancer, it has been observed that the expression of anti-inflammatory cytokines such as IL-4, IL-10 and TGF-␤ correlates with disease severity [48] . Moreover, the expression of anti-inflammatory cytokines in a cervical tumor microenvironment can lead to local immunosuppression, which is associated with deregulation of several molecules of the immune response [49] including downregulation of MHC class I expression [50][51][52] .…”

Section: Discussionmentioning

confidence: 99%

Altered HLA Class I and HLA-G Expression Is Associated with IL-10 Expression in Patients with Cervical Cancer

Rodríguez¹,

Galeano²,

Palacios

et al. 2011

Pathobiology

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Although high-risk human papillomaviruses (HPVs) are an important risk factor in the etiopathogenesis of cervical cancer, increasing evidence suggests that the ability to avoid immune surveillance seems to be linked to the transforming potential of HPV and a rapid progression to cancer. In other cancer models, IL-10 contributes to impair anti-tumor immune response either by downregulating human leukocyte antigen Class I (HLA-I) expression or by increasing HLA-G expression. To comprehend how these alterations could contribute to evasion of immune surveillance in cervical cancer, we analyzed HLA-I, HLA-G and IL-10 expressions by immunohistochemistry in 63 biopsies from patients with cervical intraepithelial neoplasia III (CIN-III) and cervical cancer. Immunohistochemistry showed absent or weak HLA-I expression in 50/59 cases. In these cases, a high percentage had loss of heterozygosis. IL-10 and HLA-G expression were observed in 46.6 and 27.6% of cases, respectively. Concurrent upregulation of IL-10 was found in 87.5% of HLA-G positive cases (p = 0.000). Similarly, a significant association between IL-10 expression and HLA-I downregulation was found (p = 0.028). Finally, we observed higher HLA-G expression in patients with HLA-I downregulation than in those with normal HLA-I expression (p = 0.004). Our results suggest that, in cervical cancer, the IL-10 expression may induce an immunosuppressive environment by upregulating HLA-G expression and downregulating HLA class I expression.

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Section: Discussionmentioning

confidence: 99%

Altered HLA Class I and HLA-G Expression Is Associated with IL-10 Expression in Patients with Cervical Cancer

Rodríguez¹,

Galeano²,

Palacios

et al. 2011

Pathobiology

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“…PCR cycling conditions were as follows: one cycle of 95 C for 3 min and 35 cycles of 95 C for 30 sec, 60 C for 1 min, and 72 C for 1 min as previously described (5,16,34). This was followed by strand elongation for 5 min at 72 C. The number of cycles and quantity of cDNA used in PCR permitted to show differences among genetic expression and a good semi-quantification among periods and strains studied.…”

Section: Methodsmentioning

confidence: 99%

Pro‐ and Anti‐Inflammatory Cytokines Produced by Human Monocytes Challenged In Vitro with Paracoccidioides brasiliensis

Kurokawa

Araújo

Soares

et al. 2007

Microbiology and Immunology

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Monocytes and macrophages play a central role in innate and adaptive immune response against systemic fungal infections. Imbalances in suppressor or stimulatory cytokine secretion caused by these cells may influence disease development, microorganism death, and the nature of the adaptive immune response. This study analyzed the monocyte cytokine profiles of healthy individuals challenged with high and low virulent strains of P. brasiliensis and mRNA cytokine expression kinetics by reverse transcription polymerase chain reaction (RT‐PCR). Peripheral blood monocytes from healthy volunteers were cultured in vitro with and without virulent (Pb18) or low virulence (Pb265) strains from P. brasiliensis viable yeast cells. Interleukin‐1 beta (IL‐1β), IL‐6, IL‐8, IL‐10, tumor necrosis factor‐alpha (TNF‐α), and transforming growth factor‐beta (TGF‐β1) were measured in culture supernatants by enzyme immunoassay (ELISA), and mRNA cytokine expression was determined by RT‐PCR at 0, 4, 8, 12, 18 and 48 hr. Both P. brasiliensis strains induced monocyte production of IL‐1β, IL‐6, IL‐10 and TNF‐α. Pb18 induced higher levels of IL‐1β, IL‐6, and IL‐10 than Pb265. IL‐8 and TGF‐β1 levels were not significantly different from those cultured without stimulus. The mRNA cytokine expression was similar to supernatant cytokines measured by ELISA. In vitro monocyte challenge with virulent P. brasiliensis strain induces earlier and higher levels of pro‐ and anti‐inflammatory cytokines than low virulence strain.

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“…17,18 Accordingly, it has been shown that type I IFNs are downregulated in keratinocytes infected with HPV16 19 and in HPV þ cervical carcinoma cell lines, 20 and IFN-g expression is significantly decreased in cervical carcinoma tissue. 21,22 Convincing evidence exists illustrating the inhibitory effects of HPV on IFNs. However, no investigations into the effect of a DNA virus, such as HPV, on IFN-k expression exist for the full spectrum of cervical disease.…”

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confidence: 99%

IFN-κ, a novel type I IFN, is undetectable in HPV-positive human cervical keratinocytes

DeCarlo

Severini

Edler

et al. 2010

Laboratory Investigation

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Interferons (IFNs) are expressed by many cell types and play a pivotal role in the generation of immune responses against viral infections. IFN-k, a novel type I IFN, displays a tight tropism for keratinocytes and specific lymphoid populations and exhibits functional similarities with other type I IFNs. The human papillomavirus (HPV), the etiological agent for cervical cancer, infects keratinocytes of the uterine cervix and has been shown to directly inhibit the IFN pathway. We evaluated IFN-k, -b, and -g gene expression in HPV-negative normal and HPV-positive pre-malignant and malignant ex vivo cervical tissue covering the entire spectrum of cervical disease. Quantitative real-time polymerase chain reaction and methods previously optimized for detecting low-expressing genes in cervical tissue were used. In contrast to IFN-b and -g, IFN-k mRNA prevalence and levels were unexpectedly higher in diseased compared with normal whole cervical tissue with highest levels observed in invasive carcinoma tissue. Strikingly, laser capture microdissection revealed an absence of IFN-k mRNA in diseased epithelium, whereas stromal IFN-k was found exclusively in diseased tissue. IFN-g and IFN-b were likewise found to be upregulated in diseased cervical stroma. Immunofluorescence supports the involvement of monocytes and dendritic cells in the stromal induction of IFNs in diseased tissue. Further, using three-dimensional raft cultures in which the viral life cycle can be mimicked, human keratinocytes transfected with full-length HPV16 displayed a significant decrease in IFN-k mRNA compared with non-transfected human keratinocytes. Altogether, these findings show that IFN-k is down-regulated in cervical keratinocytes harboring HPV, which may be a contributing factor in the progression of a cervical lesion. Interferons (IFNs) have a critical role in the generation of an innate immune response against invading pathogens and, as a consequence, are an approved therapy for many diseases 1,2 including human papillomavirus (HPV)-associated diseases. 3,4 On infection, IFNs are synthesized and secreted to evoke anti-viral, 5 anti-tumor, 6 and immunoregulatory (reviewed in Stetson and Medzhitov 7 ) activity conferring protection to neighboring cells. Two main classes of IFNs exist. The type I IFNs, consisting of IFN-a, -b, -k, -d, -e, -o, and -t, share a common receptor and downstream signaling pathways (reviewed in Pestka et al. 8 ) and are chiefly involved in generating anti-viral activity in response to pathogens. The sole member of the type II IFN subclass, IFN-g, uses a discrete type II IFN receptor, 9 distinct signaling pathways and is primarily involved in the regulation of immune and inflammatory responses. IFN-k, a newly identified type I IFN, has been shown to signal through the type I IFN pathway 10 and displays a tight tropism for keratinocytes, monocytes (MCs), and dendritic cells (DCs). 10 IFN-k has been shown to display similar anti-viral activity to other type I IFNs. 11 However, it is distinct from other type I IFNs, as it...

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Differences in cytokine mRNA profiles between premalignant and malignant lesions of the uterine cervix

Cited by 54 publications

References 27 publications

Altered HLA Class I and HLA-G Expression Is Associated with IL-10 Expression in Patients with Cervical Cancer

Altered HLA Class I and HLA-G Expression Is Associated with IL-10 Expression in Patients with Cervical Cancer

Pro‐ and Anti‐Inflammatory Cytokines Produced by Human Monocytes Challenged In Vitro with Paracoccidioides brasiliensis

IFN-κ, a novel type I IFN, is undetectable in HPV-positive human cervical keratinocytes

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