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Open Access Research article

Antagonist-mediated down-regulation of toll-like receptors increases the prevalence of human papillomavirus infection in systemic lupus erythematosus

Shui-Lian Yu1, Paul KS Chan23, Chun-Kwok Wong4, Cheuk-Chun Szeto1, Suzanne C Ho5, Karine So5, May MY Yu6, So-Fan Yim7, Tak-Hong Cheung7, Martin CS Wong8, Jo LK Cheung2, Apple CM Yeung2, Edmund K Li1 and Lai-Shan Tam1*

Author Affiliations

1 Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, 30-32 Ngan Shing Street, Shatin, New Territories, Hong Kong

2 Department of Microbioloby, Prince of Wales Hospital, The Chinese University of Hong Kong, 30-32 Ngan Shing Street, Shatin, New Territories, Hong Kong

3 The Stanley Ho Centre for Emerging Infectious Diseases, Prince of Wales Hospital, The Chinese University of Hong Kong, 30-32 Ngan Shing Street, Shatin, New Territories, Hong Kong

4 Department of Chemical Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, 30-32 Ngan Shing Street, Shatin, New Territories, Hong Kong

5 Centre of Research and Promotion of Women's Health, Prince of Wales Hospital, The Chinese University of Hong Kong, 30-32 Ngan Shing Street, Shatin, New Territories, Hong Kong

6 Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, 30-32 Ngan Shing Street, Shatin, New Territories, Hong Kong

7 Department of Obstetrics and Gynaecology, Prince of Wales Hospital, The Chinese University of Hong Kong, 30-32 Ngan Shing Street, Shatin, New Territories, Hong Kong

8 School of Public Health and Primary Care, Prince of Wales Hospital, The Chinese University of Hong Kong, 30-32 Ngan Shing Street, Shatin, New Territories, Hong Kong

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Arthritis Research & Therapy 2012, 14:R80  doi:10.1186/ar3803

Published: 18 April 2012

Abstract

Introduction

Prevalence of an abnormal Papanicolaou smear was significantly increased in lupus patients in cross-sectional studies, associated with a higher prevalence of high-risk human papillomavirus (HPV) infection. The nucleic acid-specific Toll-like receptors (TLRs) locate at the endolysosomal compartments and trigger the induction of cytokines for the innate immune response. This study evaluated whether abnormal host innate immune response in lupus patients may enhance HPV persistence.

Methods

Protein levels of TLRs 3, 7, 8 and 9 in cervical epithelial cells of lupus patients and controls with or without HPV infection were assessed using flow cytometry. Characteristics associated with the differential expression of TLRs in systemic lupus erythematosus (SLE) were elucidated. The effect and interferon-stimulated genes (ISGs) (ISG15 and Mx-1) gene expressions were then measured in oncogenic HeLa (HPV18), CaSki (HPV) and C33A (HPV negative) cell lines using flow cytometry and quantitative real-time PCR. Ex vivo productions of cytokines and interferon-gamma (IFN-γ) upon TLR ligands stimulations were subsequently measured using cytometric bead array and ELISA.

Results

For subjects with HPV infection, levels of TLR3 and TLR7 were significantly lower in lupus patients compared with controls. Significantly decreased TLRs 7, 8 and 9 levels were observed in HPV-negative SLE compared to healthy controls. For SLE with and without HPV infection, TLR7 and 9 levels were significantly lower in infected SLE than those in HPV-negative patients. Independent explanatory variables associated with down-regulation of TLR7 level included HPV infection and a higher cumulative dose of prednisolone; while a higher cumulative dose of hydroxychloroquine and HPV infection were associated with down-regulation of TLR9 level. In cervical cell lines, TLRs 3, 7, 8, 9 protein levels and antiviral ISG15 and Mx-1 gene expressions were inhibited in two oncogenic HPV types. Functional data showed that the induction of pro-inflammatory cytokines by TLR ligands (R837, ssRNA and ODN2395) was greatly impaired in CaSki and HeLa than C33A cells.

Conclusions

In conclusion, prednisolone and TLR antagonist (hydroxychloroquine) may down-regulate protein levels of TLR7 and TLR9 in lupus patients, thereby decreasing the innate immune response against HPV infection. Upon infection, HPV further down-regulate TLR7 and 9 levels for viral persistence. Furthermore, reduction of nucleic acid-sensing TLRs 7, 8 and 9 in carcinogenic HPVs ensures that the expression of inducible pro-inflammatory cytokines is minimized to prevent the expression of antiviral ISGs (ISG15 and Mx-1) on a biologically relevant antiviral response.