TLR4 Signaling Induces B7-H1 Expression Through MAPK Pathways in Bladder Cancer Cells

Qian, Yishan; Deng, Jieqiong; Geng, Lei; Xie, Haiyang; Jiang, Guoping; Zhou, Lin; Wang, Yan; Yin, Shenyong; Feng, Xiaowen; Liu, Junwei; Zhou, Ye; Zheng, Shu-Sen

doi:10.1080/07357900801941852

Cited by 93 publications

(89 citation statements)

References 20 publications

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“…Corroborative to our results, ERK activation was recently noted to be important for IFN-g-induced B7-H1 expression in multiple myeloma and dermal fibroblast cells. Thus, our results underline the important role of the MEK/ERK pathway in influencing B7-H1 expression and show, for the first time, this mode of action in human DC, which is similar to previously described mechanisms of ERK-dependent regulation of B7-H1 in myeloma, dermal fibroblasts and bladder cancer cells [48][49][50].…”

Section: Discussionsupporting

confidence: 70%

ERK/p38 MAP‐kinases and PI3K are involved in the differential regulation of B7‐H1 expression in DC subsets

Karakhanova¹,

Meisel²,

Ring³

et al. 2009

Eur J Immunol

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Regulatory molecules of the B7-H-family expressed by DC are important for immune homeostasis, but their regulation is largely unknown. When investigating the pathways regulating B7-H1 expression in monocyte-derived DC (MoDC), freshly isolated myeloid DC (mDC) and plasmacytoid DC, respectively, we showed that in MoDC and mDC B7-H1 expression was upregulated by a standard cytokine cocktail, poly I:C or LPS. MoDC utilize ERK and PI3K pathways to upregulate B7-H1 in response to cytokines, whereas p38 kinase was predominantly utilized in response to poly I:C. In mDC, ERK and p38 pathways are involved in B7-H1 regulation, and similar to MoDC, mainly p38 signaling was required for poly I:C-induced expression of B7-H1. Plasmacytoid DC responded only to CpG with upregulation of B7-H1 and in addition to p38 also utilized the PI3K and ERK pathways to regulate B7-H1 expression. As a functional consequence of B7-H1 expression on DC, we demonstrate downmodulation of IFN-c production in T cells. Thus, the differential regulation of B7-H1 on DC subsets may suppress immune responses variably, depending on the target DC population. Further analysis of the regulatory mechanisms may facilitate the development of new immunosuppressive therapies, utilizing the regulation of B7-H1 expression on DC.Key words: B7-H1 regulatory molecules . Dendritic cells . Signal transduction Supporting Information available online IntroductionMechanisms that limit undesirable T-cell activation are important for the maintenance of peripheral tolerance. In particular, the expression of positive or negative regulatory molecules on APC is crucial. In humans, the most potent type of APC are DC, which consist of myeloid and plasmacytoid subpopulations as well as Langerhans cells. Although originally defined by their potent T-cell activation capacity, DC are obviously also involved in the maintenance of peripheral tolerance and immune homeostasis, as several types of tolerogenic DC have been described [1,2].To provide signals for the induction of T-cell immunity, DC must be matured and activated with microbial agents or cytokines, among others, in order to become equipped with an appropriate set of costimulatory molecules [3]. In contrast, immature DC lack cytokine production and surface expression of several T-cell costimulatory molecules and, Ã These authors contributed equally to this work. hence, have been shown to tolerize T cells or to induce regulatory T cells [4,5].In addition, DC can also express T-cell regulatory molecules that limit immune responses and protect the body from overwhelming injury. One recently identified molecule, B7-H1 (CD274, PD-L1-programmed death receptor ligand 1), has been implicated in the downregulation of immune responses in different human diseases, such as hepatitis, chronic gastritis, renal inflammatory disease, autoimmunity and different types of cancer [6][7][8][9][10][11][12].B7-H1 is a type 1 transmembrane glycoprotein and a member of the B7 superfamily and one of two ligands for the CD28 homologue programmed death-1...

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Section: Discussionsupporting

confidence: 70%

ERK/p38 MAP‐kinases and PI3K are involved in the differential regulation of B7‐H1 expression in DC subsets

Karakhanova¹,

Meisel²,

Ring³

et al. 2009

Eur J Immunol

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“…Furthermore, TLR4 activation by LPS up-regulated B7-H1 expression in a concentration and time dependent manner (Gong et al, 2013). Qian et al also demonstrated that MAPK pathway, especially ERK pathway was involved in LPS-induced B7-H1 expression in bladder cancer cells and inferred that blocking of B7-H1 or ERK pathway may be new targeted molecular strategies for bladder cancer (Qian et al, 2008). All these results implied the associations of TLR4 and B7-H1 with UBC-related immune escape.…”

Section: Introductionmentioning

confidence: 64%

“…Previous studies showed that MAPK pathway, especially ERK pathway was involved in LPS-induced B7-H1 expression in bladder cancer cells (Qian et al, 2008). By using specific inhibitors, we studied the effect of blocking ERK pathway on B7-H1 expression and CTLs killing against T24 cells.…”

Section: Discussionmentioning

confidence: 99%

Effect of TLR4 and B7-H1 on Immune Escape of Urothelial Bladder Cancer and its Clinical Significance

Wang

Cao²,

Yang³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Background/Aim: Toll-like receptor 4 (TLR4) and B7-H1, both normally expressed restricted to immune cells, are found to be aberrantly expressed in a majority of human tumors and may play important roles in regulation of tumor immunity. It has been shown that urothelial bladder cancer (UBC) patients can manifest tumoral immune escape which may be a potential critical factor in tumor pathogenesis and progression. However, so far, the mechanisms of UBC-related immune escape have not been clarified. The aim of this study was to investigate the effect of TLR4 and B7-H1 on immune escape of UBC. Methods: Bladder cancer T24 cells were pre-incubated with LPS and co-cultured with tumor specific CTLs. CTL cytotoxicity and apoptosis rates were measured by MTT assay and flow cytometry, respectively. The effects of an ERK inhibitor on B7-H1 expression and CTL cytotoxicity against T24 cells were also evaluated. In addition, TLR4, B7-H1 and PD-1 protein expression was analyzed by immunohistochemistry in 60 UBC specimens and 10 normal urothelia. Results: TLR4 activation protected T24 cells from CTL killing via B7-H1 overexpression. However PD98059, an inhibitor of ERK, enhanced CTL killing of T24 cells by reducing B7-H1 expression. TLR4 expression was generally decreased in UBC specimens, while B7-H1 and PD-1 were greatly overexpressed. Moreover, expression of both B7-H1 and PD-1 was significantly associated with UICC stage and WHO grade classification. Conclusions: TLR4 and B7-H1 may contribute to immune escape of UBC. Targeting B7-H1 or the ERK pathway may offer new immunotherapy strategies for bladder cancer.

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“…TLR-4, which was the first described one among TLRs, whose expression was identified not only in immune cells, but also in many kinds of malignant cells (Qian et al, 2008). The role of TLR-4 in cancer seems discrepancy according to several previous studies.…”

Section: Discussionmentioning

confidence: 99%

Curcumin Inhibits MHCC97H Liver Cancer Cells by Activating ROS/TLR-4/Caspase Signaling Pathway

Li²,

Liu³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Curcumin can inhibit proliferation of liver cancer cells by inducing apoptosis, but the specific signaling pathways involved are not completely clear. Here, we report that curcumin inhibited proliferation of MHCC97H liver cancer cells by induction of apoptosis in a concentration dependent manner via stimulating intracellular reactive oxygen species (ROS) generation. Also, we showed that increased intracellular ROS formation activated the TLR-4/MyD-88 signaling pathway, resulting in activation of caspase-8 and caspase-3, which eventually led to apoptosis in MHCC97H cells. These results showed that as an prooxidant, curcumin exerts anti-cancer effects by inducing apoptosis via the TLR-4/MyD-88 signaling pathway.

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TLR4 Signaling Induces B7-H1 Expression Through MAPK Pathways in Bladder Cancer Cells

Cited by 93 publications

References 20 publications

ERK/p38 MAP‐kinases and PI3K are involved in the differential regulation of B7‐H1 expression in DC subsets

ERK/p38 MAP‐kinases and PI3K are involved in the differential regulation of B7‐H1 expression in DC subsets

Effect of TLR4 and B7-H1 on Immune Escape of Urothelial Bladder Cancer and its Clinical Significance

Curcumin Inhibits MHCC97H Liver Cancer Cells by Activating ROS/TLR-4/Caspase Signaling Pathway

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