Article ID Journal Published Year Pages File Type
1931156 Biochemical and Biophysical Research Communications 2011 7 Pages PDF
Abstract

IGFBP-5 is known to be involved in various cell phenomena such as proliferation, differentiation, and apoptosis. However, the exact mechanisms by which IGFBP-5 exerts its functions are unclear. In this study, we demonstrate for the first time that IGFBP-5 is a TNFR1-interacting protein. We found that ectopic expression of IGFBP-5 induced TNFR1 gene expression, and that IGFBP-5 interacted with TNFR1 in both an in vivo and an in vitro system. Secreted IGFBP-5 interacted with GST-TNFR1 and this interaction was blocked by TNF-α, demonstrating that IGFBP-5 might be a TNFR1 ligand. Furthermore, conditioned media containing secreted IGFBP-5 inhibited PMA-induced NF-κB activity and IL-6 expression in U-937 cells. Coimmunoprecipitation assays of TNFR1 and IGFBP-5 wild-type and truncation mutants revealed that IGFBP-5 interacts with TNFR1 through its N- and L-domains. However, only the interaction between the L-domain of IGFBP-5 and TNFR1 was blocked by TNF-α in a dose-dependent manner, suggesting that the L-domain of IGFBP-5 can function as a TNFR1 ligand. Competition between the L-domain of IGFBP-5 and TNF-α resulted in inhibition of TNF-α-induced NF-κΒ activity. Taken together, our results suggest that the L-domain of IGFBP-5 is a novel TNFR1 ligand that functions as a competitive TNF-α inhibitor.

Research highlights► Binding assays demonstrated that secreted- and cellular-IGFBP-5 interacted with TNFR1. ► The interaction between IGFBP-5 and TNFR1 was inhibited by TNF-α and was blocked TNF-α-activated NF-κB activity. ► IGFBP-5 interacted with TNFR1 through its N- and L-domains but the binding of L-domain to TNFR1 was blocked by TNF-α. ► Competition between the L-domain of IGFBP-5 and TNF-α blocked TNF-α-induced NF-κB activity. ► This study suggests that the L-domain of IGFBP-5 is a novel TNFR1 ligand that functions as a competitive TNF-α inhibitor.

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