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Toll-Like Receptors 7, 8, and 9 Expression and Function in Primary Human Cervical Cancer Langerhans Cells Evidence of Anergy

Kumar, Mahesh M and Adurthi, Sreenivas and Ramachandran, Surya and Mukherjee, Geetashree and Joy, Omana and Krishnamurthy, H and Krishna, Sudhir and Bafna, UD and Uma, Devi K and Jayshree, RS (2013) Toll-Like Receptors 7, 8, and 9 Expression and Function in Primary Human Cervical Cancer Langerhans Cells Evidence of Anergy. In: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER, 23 (1). pp. 184-192.

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Official URL: http://dx.doi.org/10.1097/IGC.0b013e31827a2003

Abstract

Objective: Human papillomavirus oncoproteins E6 and E7 down modulate Toll-like receptor (TLR) 9 expression in infected keratinocytes. We explored the status of expression and function of TLR7, TLR8, and TLR9 in primary human Langerhans cells (LCs) isolated from cervical tumors. Methodology: Single-cell suspensions were made from fresh tissues of squamous cell carcinoma (International Federation of Gynecology and Obstetrics stage IB2); myeloid dendritic cells were purified using CD1c magnetic activated cell separation kits. Langerhans cells were further flow sorted into CD1a(+)CD207(+) cells. Acute monocytic leukemia cell line THP-1-derived LCs (moLCs) formed the controls. mRNA from flow-sorted LCs was reverse transcribed to cDNA and TLR7, TLR8, and TLR9 amplified. Monocyte-derived Langerhans cells and cervical tumor LCs were stimulated with TLR7, TLR8, and TLR9 ligands. Culture supernatants were assayed for interleukin (IL) 1 beta, IL-6, IL-10, IL-12p70, interferon (IFN) alpha, interferon gamma, and tumor necrosis factor (TNF) alpha by Luminex multiplex bead array. Human papillomavirus was genotyped. Results: We have for the first time demonstrated that the acute monocytic leukemia cell line THP-1 can be differentiated into LCs in vitro. Although these moLCs. expressed all the 3 TLRs, tumor LCs expressed TLR7 and TLR8, but uniformly lacked TLR9. Also, moLCs secreted IL-6, IL-1 beta, and tumor necrosis factor alpha to TLR8 ligand and interferon alpha in response to TLR9 ligand; in contrast, tumor LCs did not express any cytokine to any of the 3 TLR ligands. Human papillomavirus type 16 was one of the common human papillomavirus types in all cases. Conclusions: Cervical tumor LCs lacked TLR9 expression and were functionally anergic to all the 3: TLR7, TLR8, and TLR9 ligands, which may play a crucial role in immune tolerance. The exact location of block(s) in TLR7 and TLR8 signaling needs to be investigated, which would have important immunotherapeutic implications.

Item Type: Journal Article
Additional Information: Copyright for this article belongs to LIPPINCOTT WILLIAMS & WILKINS,USA
Keywords: Langerhans cells;TLR7;TLR8;TLR9;Cervical cancer;CpG ODN;Human papillomavirus type 16;Immune tolerance;Toll-like receptor
Department/Centre: Division of Biological Sciences > Biochemistry
Depositing User: Francis Jayakanth
Date Deposited: 26 Feb 2013 12:21
Last Modified: 26 Feb 2013 12:21
URI: http://eprints.iisc.ac.in/id/eprint/45855

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