TNF upregulates peptidoglycan recognition protein 1 in esophageal cancer cells to clear the path to its signaling: Making the "enemy" a friend

TNF, CCN1, and peptidoglycan recognition protein 1 (PGLYRP1) are often found together in the inflammatory tissue. While TNF and CCN1 promote tissue regeneration, PGLYRP1 protects it from bacterial infection. In fibroblasts, CCN1 was reported to support TNF in apoptosis induction while PGLYRP1 was found to compete with TNF for binding to TNFR1. When PGLYRP1 binds to TNFR1 by itself, it silences the receptor, but if HSP70 joins them, it leads to cell death. In cancer cells, however, CCN1 was found to antagonize TNF signaling by increasing the extracellular pool of TNFR1. In this study, we assessed their relationship in the esophageal cancer cells and found a more complex liaison among them. At first, TNF highly upregulated PGLYRP1 expression but downregulated CCN1. Secondly, PGLYRP1 bound TNFR1 and HSP70 both intracellularly and extracellularly, but TNF only promoted their extracellular interaction. Lastly, the knockdown of PGLYRP1 impaired TNF signaling. Taken together, this study shows that CCN1 interrupts TNF signaling by increasing the extracellular TNFR1 species while TNF fights back by upregulating PGLYRP1 to absorb them.