Deubiquitinating enzymes (DUBs) appear to be critical regulators of a multitude of processes Such as proliferation, apoptosis, differentiation, and inflammation. We have recently demonstrated that a DUB of ubiquitin carboxyl terminal hydrolase L1 (UCH-L1) inhibits Vascular lesion formation via suppressing inflammatory responses in vasculature However, the precise underlying mechanism remains to be defined. Herein. we report that a posttranscriptional up-regulation of UCH-L1 provides a negative feedback to tumor necrosis factor alpha (TNF alpha)-mediated activation of extracellular signal-regulated kinases (ERIO and proliferation in vascular smooth muscle cells (VSMCs). In rat adult VSMCs. adenoviral overexpression of UCH-L1 inhibited TNF alpha-induced activation of ERK and DNA synthesis. In contrast, overexpression of UCH-L1 did not affect platelet derived growth factor (PDGF)-induced VSMC proliferation and activation of growth stimulating cascades including ERK. TNF alpha hardly altered UCH-L1 mRNA expression and stability, however, up-regulated UCH-L1 protein expression via increasing UCH-L1 translation. These results uncover a novel mechanism by which UCH-L1 suppresses vascular Inflammation (C) 2009 Elsevier Inc. All rights reserved.