Cancer-derived immunoglobulin G promotes LPS-induced proinflammatory cytokine production via binding to TLR4 in cervical cancer cells.

Juping Wang,Danyi Lin,Jiang Gu,Hui Peng,Jimin Shao

doi:10.18632/oncotarget.2359

Juping Wang, Danyi Lin + Show 3 more

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https://doi.org/10.18632/oncotarget.2359

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Abstract

Numerous studies have shown that various cancer cells express immunoglobulin G (IgG). However, the function of cancer-derived IgG and the underlying mechanism remain unclear. In this study, we demonstrated that IgG expression was significantly altered after exposure to LPS in cervical cancer cells, suggesting that IgG was potentially involved in regulation of TLR4 signaling. Reduction of IgG attenuated LPS-induced proinflammatory cytokine production. The phosphorylation levels of NF-κB and MAPK were consistently suppressed by knockdown of IgG, which in turn impaired NF-κB nuclear translocation and the activity of NF-κB responsive element. Furthermore, we found that IgG was recruited to TLR4 in the cytoplasm after LPS stimulation, and IgG silencing inhibited LPS-initiated proinflammatory cytokine production through downregulating TLR4 expression. Similar results were obtained in a mouse model of endotoxemia and human tissues. Taken together, our findings demonstrate that IgG is a positive regulator of LPS-induced proinflammatory cytokine production by binding to TLR4 and enhancing its expression. TLR4 signaling plays a positive role in the development of many inflammation induced cancers such as cervical cancer. Our study strongly indicates that IgG may promote cervical cancer cell proliferation through enhancing TLR4 signaling. IgG may be a novel therapeutic target in treating inflammation mediated cancers.

Highlights

Toll-like receptors (TLRs) play a key role in innate immune system by recognizing conserved components of invading microbial pathogens [1,2,3]
To explore the role of immunoglobulin G (IgG) in cervical cancer cells response to LPS stimulation, we examined whether IgG expression could be induced by LPS in cervical cancers cells
To investigate the kinetics of the regulation of IgGγ expression in HeLa cells induced by LPS, we examined IgGγ expression in HeLa cells treated with LPS for different time periods with immunoblot and real-time quantitative reverse transcription PCR (RT-qPCR)

Summary

Introduction

Toll-like receptors (TLRs) play a key role in innate immune system by recognizing conserved components of invading microbial pathogens [1,2,3]. Among TLRs, TLR4, a critical member, initiates innate immune responses by activating signaling pathways dependent on the adaptor protein myeloid differentiating factor 88 (MyD88) or the adaptor toll/il-1r domain-containing adaptor inducing interferon-β (TRIF). The binding between TLR4 and MyD88 leads to the activation of nuclear factor κB (NF-κB). While the interaction between TLR4 and TRIF activates interferon regulatory factor 3 (IRF3) and produces type I interferon (IFN) such as IFN-α and IFN-β [7, 8]. TLR4 expression on various cancer cells suggests that TLR4 signaling may play a crucial role in cancer development and immunity

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