Coiled-coil domain containing 3 (CCDC3) represses tumor necrosis factor-α/nuclear factor κB-induced endothelial inflammation

Abstract

Coiled-coil domain containing 3 (CCDC3) is a newly identified secretory protein that is expressed in vascular endothelial cells (ECs) and adipose tissues. Here, we investigate the role of CCDC3 in tumor necrosis factor (TNF)-α-induced inflammatory response in ECs. Our results show that stable overexpression of CCDC3 decreases, while stable knockdown of the endogenous CCDC3 increases TNF-α-induced expression of vascular cell adhesion molecule-1 (VCAM-1) at the mRNA and protein level in ECs. The IκB kinase inhibitor Bay 11-7082 completely blocks TNF-α-induced expression of VCAM-1, confirming that TNF-α-induced expression of VCAM-1 in ECs is nuclear factor κB (NF-κB) dependent. Stable overexpression of CCDC3 decreases TNF-α-induced p65 and p50 nuclear translocation and NF-κB transcriptional activity, suggesting that CCDC3 inhibits TNF-α-induced NF-κB activation in ECs. Similar to CCDC3 overexpression, both CCDC3-containing conditioned medium (CM) and purified CCDC3 decrease TNF-α-induced expression of VCAM-1 in receiving ECs, suggesting a paracrine/autocrine function of CCDC3. Interestingly, CCDC3 in CM can enter the receiving ECs. Taken together, our work demonstrates that CCDC3 represses TNF-α/NF-κB-induced pro-inflammatory response in ECs, providing an insight into the functional role of CCDC3.

Keywords: Coiled-coil domain containing 3 (CCDC3); Endothelial inflammation; Nuclear factor κB (NF-κB); Tumor necrosis factor α (TNF-α); Vascular cell adhesion molecule-1 (VCAM-1).