Cancer-derived immunoglobulin G promotes LPS-induced proinflammatory cytokine production via binding to TLR4 in cervical cancer cells
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1 Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou China.
2 Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Department of Pathology, Shantou University Medical College, Shantou, China.
* These authors contributed equally to this work
Dr. Jiang Gu, e-mail: firstname.lastname@example.org
Dr. Jimin Shao, e-mail: email@example.com
Keywords: IgG; cancer; promote; TLR4; proinflammatory cytokine
Received: June 22, 2014 Accepted: August 17, 2014 Published: August 23, 2014
Abbreviations: IgG, immunoglobulin; TLR4, toll-like receptor 4; MyD88, myeloid differentiating factor 88; TRIF, toll/il-1r domain-containing adaptor inducing interferon-β; NF-κB, nuclear factor κB; MAPK, mitogen-activated protein kinase; TNF-α, tumor necrosis factor; IL, interleukin; IRF3, interferon regulatory factor 3; IFN, interferon; VHDJH, the heavy chain variable segment (VH), diversity segment (D), and joining segment (JH) recombination; Oct-2, octamer-related protein-2; NeuAc, N-acetylneuraminic acid; LPS, lipopolysaccharide; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; RT-qPCR, real-time quantitative reverse transcription PCR; IGHG1, immunoglobulin heavy constant gamma 1; IKKα/β, IκB kinase α/β; IκBα, inhibitory NF-κB α; IRAK1, interleukin-1 receptor-associated kinase 1; TRAF6, TNF receptor-associated factor 6; DAPI, 4', 6-diamidino-2-phenylindole
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.
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