Pathways of IFN-alpha Activation in Patients with Cervical Intraepithelial Neoplasia (CIN).

Kézia Jesus Aguiar Ferreira,Carolina Guissoni Campos,Márcia Antoniazi Michelin,Eddie Fernando Cândido Murta,Nelson Ranieri Tirone,Léticia Montes Stark,Jéssica Ferreira Vieira

doi:10.1055/s-0041-1735301

Abstract

The aim of the present study was to compare the local and systemic expression of the factors linked to the interferon alpha (IFN-α) activation pathway in different degrees of cervical intraepithelial neoplasia (CIN) and cervical cancer. A total of 128 patients with CIN I, CIN II, CIN III and cervical cancer was evaluated. The real-time polymerase chain reaction (RT-PCR) technique was used to evaluate the gene expression of IFNR1, IFNR2, IFN-α, oligoadenylate synthase (2'5'OAS), cytokine signal suppressor 1 (SOCS) 1, SOCS3, signal transducer and transcription activator 1 (STAT1), and IRF9 from 128 biopsies. A total of 46 out of 128 samples were evaluated by flow cytometry for IFNAR1, IFNAR2, STAT1, IRF7 and IFN-α in peripheral blood cells. Patients with CIN II and III (63 samples) had a low local expression of IFNR1, but not IFNR2. Patients with some degree of injury showed high expression of SOCS1 and SOCS3. Systemically, patients with CIN II and III (20 samples) had a significant increase in IFNR1, IFNR2, STAT1, IRF7, and IFN-α in helper, cytotoxic T lymphocytes, and in monocytes. Patients with high-grade lesions have increased systemic expression of IFN-α and its activation pathways in helper and cytotoxic T lymphocytes, as well as in monocytes due to an exacerbation of the immune response in these patients. This phenomenon is not accompanied by resolution of the lesion due to a defect in the IFN-α activation pathway that revealed by low local IFNAR1 expression and high local expression of SOCS1 and SOCS3.

Highlights

The possibility of early screening and treating neoplastic lesions was of considerable importance in reducing the incidence and deaths from invasive cervical cancer
For the IFNR1 and IFNR2 receptors (►Figure 1B, C), in each cell population compared (CD4þ, CD8þ, and CD14þ), the IFNR1 and IFNR2 receptors were increased in the Cervical intraepithelial neoplasms (CIN) II and CIN III groups compared to the Control group IFNR1þ CD4þ (p 1⁄4 0.0002); IFNR1þ CD8þ (p 1⁄4 0.0011); IFNR1þ CD14þ (p 1⁄4 0.0011); IFNR2þ CD4þ (p 1⁄4 0.0003); IFNR2þ CD8þ (p 1⁄4 < 0.0001); and IFNR2þ CD14þ (p 1⁄4 0.0009)
Transcription factors were analyzed in the T helper lymphocytes, T CTL lymphocytes, and monocytes (►Figure 2). we observed a significant increase in CIN II and CIN III compared to the Control group (►Figure 2A) for both signal transducer and transcription activator 1 (STAT1) (p 1⁄4 0.0031) and interferon regulatory factor (IRF)-7 (p 1⁄4 0.0008)

Summary

Introduction

The possibility of early screening and treating neoplastic lesions was of considerable importance in reducing the incidence and deaths from invasive cervical cancer. Grade I should be treated to preserve the cervix, while for grades II and III, local excision of the cervix has been considered as a therapeutic intervention because the latter has the potential for progression to invasive cancer (CA).[1] this imposes risks during pregnancy, such as increased prematurity and abortions.[2]. Alternatives for treatment have been evaluated, such as the use of interferons (IFNs), which have been recognized as extremely important cytokines for human health, since they have therapeutic potential against viral actions.[3,4] As a fundamental part of the immune response, interferon alpha (IFN-α) is able to inhibit exacerbated cell proliferation through its signaling pathways. It is able to suppress the expression of oncogenes and to promote apoptosis.[5]

Methods

Results

Discussion

Conclusion