Forward and Reverse Signaling Mediated by Transmembrane Tumor Necrosis Factor-Alpha and TNF Receptor 2: Potential Roles in an Immunosuppressive Tumor Microenvironment.

Yang Qu,Hui Li,Gang Zhao

doi:10.3389/fimmu.2017.01675

Yang Qu, Hui Li + Show 1 more

Open Access

https://doi.org/10.3389/fimmu.2017.01675

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Abstract

Tumor necrosis factor-alpha (TNF-α) is a pleiotropic inflammatory cytokine produced mainly by activated macrophages, lymphocytes and other cell types. Two distinct forms of TNF-α have been identified: soluble TNF-α (sTNF-α) and transmembrane TNF-α (mTNF-α). mTNF-α, which is the precursor of sTNF-α, can be cleaved by the TNF-α converting enzyme (TACE) and is released as sTNF-α. sTNF-α binds primarily to TNF receptor 1 (TNFR1) and plays an important role in the inflammatory immune response, whereas mTNF-α interacts primarily with TNF receptor 2 (TNFR2) and mediates the promotion of cellular proliferation and survival and other biological effects. It has been reported that the interaction between mTNF-α and TNFR2 induces bi-directional (forward and reverse) signaling in both mTNF-α- and TNFR2-expressing cells. Increasing evidence shows that the forward and reverse signaling mediated by mTNF-α and TNFR2 might play a significant role in the tumor microenvironment. In this review, the role of the crosstalk between mTNF-α and TNFR2 in the tumor microenvironment will be discussed.

Highlights

Specialty section: This article was submitted to Immunological Tolerance and Regulation, a section of the journal Frontiers in Immunology
Increasing evidence shows that the forward and reverse signaling mediated by mTNF-α and TNF receptor 2 (TNFR2) might play a significant role in the tumor microenvironment
In 1988, Kriegler et al [20] announced that they had identified and characterized a novel, rapidly inducible cell surface cytotoxic integral transmembrane form of TNF-α that could explain the complex physiology of the molecule. mTNF-α is a stable homotrimer and is the precursor form of soluble TNF-α (sTNF-α). mTNF-α can be cleaved by TNF-α converting enzyme (TACE) and released as sTNF-α into the circulation to exert its biological function via type 1 and 2 TNF-α receptors [6]

Summary

Introduction

Specialty section: This article was submitted to Immunological Tolerance and Regulation, a section of the journal Frontiers in Immunology. It has been reported that the interaction between mTNF-α and TNFR2 induces bi-directional (forward and reverse) signaling in both mTNF-α- and TNFR2-expressing cells. As a receptor, mTNF-α mediates reverse signals back into the mTNF-α-bearing cells, such as T cells, monocytes/macrophages, and NK cells, to regulate the immune responses of these different cell types [5].

Results

Conclusion