Quantitative analysis of IL-10 and IFN-? mRNA levels in normal cervix and human papillomavirus type 16 associated cervical precancer

El-Sherif, A; Seth, Rashmi; Tighe, Patrick J.; Jenkins, David

doi:10.1002/path.929

Cited by 69 publications

(54 citation statements)

References 47 publications

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“…10 In addition, IFN-k mRNA was absent in raft cultures containing collagen and fibroblasts only (stroma equivalent), that is without keratinocytes, MCs or DCs in this study, which further supports the specific role of lymphoid populations in the stromal IFN-k induction. In line with IL-10 mRNA levels in this study, IL-10 has previously been found to be elevated in diseased cervical tissue 41 and in peripheral blood mononuclear cells of patients with extensive cervical disease. 42 However, the cause of the IL-10 elevation had not been addressed in these studies.…”

Section: Discussionsupporting

confidence: 88%

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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Section: Discussionsupporting

confidence: 88%

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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“…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).…”

Section: Discussionmentioning

confidence: 99%

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

Wendel

Kaldensjö²,

Peterson³

et al. 2010

Int J Oncol

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Abstract. Persistent human papillomavirus (HPV) infection is a prerequisite for cervical cancer and results from bypassing the local immune response. Twenty-four volunteers underwent an ectocervical biopsy, Pap smear, tests for sexually transmitted infections including HIV and HPV genotyping. All answered a questionnaire regarding medical history. Repeat Pap smear and HPV genotyping was performed 9-26 months later. Quantitative reverse transcriptase (qRT-)PCR was used to assess expression of CD3, CD4, CD8, CD19, CD27, IL-2, IL-12, IL-4, IL-10, IL-17, HLA-DR·, TGFß, IFNÁ, PD-1, PD-L1, CTLA-4, LAG3, IgA, IgG, CCR5, CCL5/RANTES and the IL-7 receptor in the biopsies. Eleven of 24 volunteers were HPV DNA-positive at baseline. Four of 10 were infected with a persistent HPV genotype at followup. All target molecules were successfully amplified and quantified except for IL-4. We found no difference in mRNA expression of these molecules when comparing HPV DNApositive and -negative women, neither when comparing persistently infected individuals or those who cleared the infection. However, mRNA expression of the B cell phenotypic marker CD19 was higher in women using hormonal contraception than those not (p<0.05). HPV infection does not evoke a local inflammatory immune response in the ectocervix measurable with qRT-PCR. Hormonal contraception may influence B cell activity in the cervix.

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“…The results showed that only IFN-γ positive results were significantly associated with clearance of HR-HPV after 12 months of follow-up (Song et al, 2008). The microdissections of 11 normal cervixes and 25 HPV-16 positive CIN cervixes were studied and the researchers suggested that reduced epithelial and sub-epithelial IFN-γ, as well as increased sub-epithelial IL-10 synthesis, may play a role in the development and progression of HPV16 associated cervical pre-cancer (El-Sherif et al, 2001). Alterations of the local cervical immune environment in cervical cancer were demonstrated in a study that analyzed the presence of various cytokines in CVLs of 22 healthy volunteers, 63 CIN patients and 33 cervical cancer patients.…”

Section: Discussionmentioning

confidence: 99%

Local Cervical Immunity in Women with Low-grade Squamous Intraepithelial Lesions and Immune Responses After Abrasion

Ekalaksananan

Malat²,

Pientong³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Minor trauma to the uterine cervix is supposed to induce local immunity to prevent cervical lesions caused by human papillomavirus (HPV) infection. This study aimed to investigate the local cervical immunity in women with low grade squamous intraepithelial lesion (LSIL) and effects of abrasion after cryosurgery or Pap smear. One hundred women with LSIL and known results of HPV detection were recruited. HPV positive women were randomly divided according to abrasion into cryotherapy and Pap smear observation groups. Cervical tissues and cervico-vaginal lavage (CVL) were collected at 6 and 12 months after allocation. The levels of cytokines at first recruitment were compared with cytokine levels at 6 months after abrasions. The mRNA of IFN-γ , TNF-α and IL-10 in cervical tissues and these cytokines secreted in CVL were determined using real time PCR and ELISA, respectively. Anti-HPV16 IgG and IgA antibodies in CVL were assessed by western blotting. At first recruitment of women with LSIL (100 cases), IL-10 mRNA and cytokine in HPV positive group (60 cases) was significantly higher than negative group (40 cases). IFN-γ and TNF-α mRNA level in both groups were comparable but their secretions in CVL were significantly increased in HPV negative group. After abrasion for 6 months in HPV-positive women, all mRNA and secreted cytokines were changed, but no significant difference was observed between cryotherapy and observation groups. When individuals were compared between first recruitment and after abrasion for 6 months, IFN-γ mRNA and anti-HPV16 L1 IgA antibodies were significantly increased in the cryotherapy group. The results suggest that modulation of local cervical immunities by abrasion might promote different effects in clearance of HPV-related cytological abnormalities.

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Quantitative analysis of IL-10 and IFN-? mRNA levels in normal cervix and human papillomavirus type 16 associated cervical precancer

Cited by 69 publications

References 47 publications

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

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

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

Local Cervical Immunity in Women with Low-grade Squamous Intraepithelial Lesions and Immune Responses After Abrasion

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