title: A pro-inflammatory role of deubiquitinating enzyme cylindromatosis (CYLD) in vascular smooth muscle cells.
abstract: CYLD, a deubiquitinating enzyme (DUB), is a critical regulator of diverse cellular processes, ranging from proliferation and differentiation to inflammatory responses, via regulating multiple key signaling cascades such as nuclear factor kappa B (NF-κB) pathway. CYLD has been shown to inhibit vascular lesion formation presumably through suppressing NF-κB activity in vascular cells. However, herein we report a novel role of CYLD in mediating pro-inflammatory responses in vascular smooth muscle cells (VSMCs) via a mechanism independent of NF-κB activity. Adenoviral knockdown of Cyld inhibited basal and the tumor necrosis factor alpha (TNFα)-induced mRNA expression of pro-inflammatory cytokines including monocyte chemotactic protein-1 (Mcp-1), intercellular adhesion molecule (Icam-1) and interleukin-6 (Il-6) in rat adult aortic SMCs (RASMCs). The CYLD deficiency led to increases in the basal NF-κB transcriptional activity in RASMCs; however, did not affect the TNFα-induced NF-κB activity. Intriguingly, the TNFα-induced IκB phosphorylation was enhanced in the CYLD deficient RASMCs. While knocking down of Cyld decreased slightly the basal expression levels of IκBα and IκBβ proteins, it did not alter the kinetics of TNFα-induced IκB protein degradation in RASMCs. These results indicate that CYLD suppresses the basal NF-κB activity and TNFα-induced IκB kinase activation without affecting TNFα-induced NF-κB activity in VSMCs. In addition, knocking down of Cyld suppressed TNFα-induced activation of mitogen activated protein kinases (MAPKs) including extracellular signal-activated kinases (ERK), c-Jun N-terminal kinase (JNK), and p38 in RASMCs. TNFα-induced RASMC migration and monocyte adhesion to RASMCs were inhibited by the Cyld knockdown. Finally, immunochemical staining revealed a dramatic augment of CYLD expression in the injured coronary artery with neointimal hyperplasia. Taken together, our results uncover an unexpected role of CYLD in promoting inflammatory responses in VSMCs via a mechanism involving MAPK activation but independent of NF-κB activity, contributing to the pathogenesis of vascular disease.
authors.affiliation: Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Liu
authors.forename: Jiaju
authors.initials: J
authors.lastname: Lv
authors.forename: Liping
authors.initials: L
authors.lastname: Han
authors.forename: Tomonaga
authors.initials: T
authors.lastname: Ichikawa
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Wang
authors.forename: Siying
authors.initials: S
authors.lastname: Li
authors.forename: Xing Li
authors.initials: XL
authors.lastname: Wang
authors.forename: Dongqi
authors.initials: D
authors.lastname: Tang
authors.forename: Taixing
authors.initials: T
authors.lastname: Cui
mesh_terms: D000818:Animals; D001167:Arteritis / Q000201:enzymology* / Q000473:pathology; D002448:Cell Adhesion; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D003331:Coronary Vessels / Q000201:enzymology / Q000473:pathology; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000502:physiology*; D000074749:Deubiquitinating Enzyme CYLD; D055785:Gene Knockdown Techniques; D006965:Hyperplasia / Q000201:enzymology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009000:Monocytes / Q000201:enzymology / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D058426:Neointima / Q000201:enzymology / Q000473:pathology; D012259:Ribonuclease, Pancreatic / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D020929:Mitogen-Activated Protein Kinase Kinases; C099439:Ang2 protein, mouse; D012259:Ribonuclease, Pancreatic; C511601:CYLD protein, mouse; D000074749:Deubiquitinating Enzyme CYLD; D003546:Cysteine Endopeptidases