title: 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.
authors.affiliation: Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Abul Kalam
authors.initials: AK
authors.lastname: Azad
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Subhadeep
authors.initials: S
authors.lastname: Chakrabarti
authors.affiliation: Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Sandra T
authors.initials: ST
authors.lastname: Davidge
authors.affiliation: Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada; Department of Obstetrics and Gynecology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada. Electronic address: yangxin@ualberta.ca.
authors.forename: YangXin
authors.initials: Y
authors.lastname: Fu
mesh_terms: D019898:Autocrine Communication / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism*; D019899:Paracrine Communication / Q000187:drug effects; D011506:Proteins / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: C000594569:CCDC3 protein, human; D017077:Culture Media, Conditioned; D016328:NF-kappa B; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1
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)