Tumor necrosis factor receptor 1 associates with CD137 ligand and mediates its reverse signaling

作者：Moh Mei Chung; Lorenzini Paolo Alberto; Gullo Charles; Schwarz Herbert^*

来源：The FASEB Journal, 2013, 27(8): 2957-2966.

DOI：10.1096/fj.12-225250

• TNFR1
• THP-1 cells
• monocytes

Reverse signaling through CD137 ligand (CD137L) potently activates monocytes. However, the underlying mechanism is not well elucidated. This study provides evidence that tumor necrosis factor receptor 1 (TNFR1) acts as a coreceptor for CD137L and mediates CD137L signaling. CD137L colocalizes with TNFR1 on the plasma membrane and binds directly to TNFR1 via its extracellular domain. Using the human monocytic THP-1 cell line, we demonstrate that engagement of CD137L by recombinant CD137 protein promotes cell adhesion, apoptosis, expression of CD14, and production of IL-8 and tumor necrosis factor (TNF). Concomitantly, the expression of TNFR1 protein is down-regulated in response to CD137L activation, due to enhanced extracellular release and internalization of TNFR1. Activation of TNFR1 by TNF protein additively augments CD137L-induced IL-8 expression. Conversely, inhibition of TNFR1 activity by a TNFR1-neutralizing antibody inhibits CD137L-mediated cell adhesion, cell death, CD14 expression, and IL-8 production. Taken together, these data show that TNFR1 associates with CD137L and is required for CD137L reverse signaling.Moh, M. C., Lorenzini, P. A., Gullo, C., Schwarz, H. Tumor necrosis factor receptor 1 associates with CD137 ligand and mediates its reverse signaling.

• 出版日期2013-8