Herpesvirus entry mediator (HVEM) attenuates signals mediated by the lymphotoxin beta receptor (LTbetaR) in human cells stimulated by the shared ligand LIGHT

Bechill, J.; Muller, W. J.

Mol Immunol. 2014 Jul 2; 62(1):96-103

Abstract

Signals mediated by members of the tumor necrosis factor receptor superfamily modulate a network of diverse processes including initiation of inflammatory responses and altering cell fate between pathways favoring survival and death. Although such pathways have been well-described for the TNF-alpha receptor, less is known about signaling induced by the TNF superfamily member LIGHT and how it is differentially altered by expression of its two receptors LTbetaR and HVEM in the same cell. We used cell lines with different relative expression of HVEM and LTbetaR to show that LIGHT-induced signals mediated by these receptors were associated with altered TRAF2 stability and RelA nuclear translocation. Production of the inflammatory chemokine CXCL10 was primarily mediated by LTbetaR. Higher expression of HVEM was associated with cell survival, while unopposed LTbetaR signaling favored pathways leading to apoptosis. Importantly, restoring HVEM expression in cells with low endogenous expression recapitulated the phenotype of cells with higher endogenous expression. Together, our data provide evidence that relative expression of HVEM and LTbetaR modulates canonical NF-kappaB and pro-apoptotic signals stimulated by LIGHT.

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