TRIM14 promotes endothelial activation via activating NF-κB signaling pathway

Endothelial activation by proinflammatory cytokines is closely associated to the pathogenesis of atherosclerosis and other vascular diseases;however, the molecular mechanisms controlling endothelial activation are not fully understood. Here we identify TRIM14 as a new positive regulator of endothelial activation via activating NF-κB signal pathway. TRIM14 is highly expressed in human vascular endothelial cells (ECs) and markedly induced by inflammatory stimuli such as TNF-α, IL-1β, and LPS. Overexpression of TRIM14 significantly increased the expression of adhesion molecules such as VCAM-1, ICAM-1, E-selectin, and cytokines such as CCL2, IL-8, CXCL-1, and TNF-α in activated ECs and by which it facilitated monocyte adhesion to ECs. Conversely, knockdown of TRIM14 has opposite effect on endothelial activation. Upon TNF-α stimulation, TRIM14 is recruited to IKK complex via directly binding to NEMO and promotes the phosphorylation of IκBα and p65, which is dependent on its K63-linked ubiquitination. Meanwhile, p65 can directly bind to the promoter regions of human TRIM14 gene and control its mRNA transcription. Finally, TRIM14 protein level is significantly upregulated in mouse and human atheroma compared to normal arteries. Taken together, these results indicate that TRIM14-NF-κB forms a positive feedback loop to enhance EC activation and TRIM14 may be a potential therapeutic target for vascular inflammatory diseases such as atherosclerosis.

Central role of myeloid MCPIP1 in protecting against LPSinduced inflammation and lung injury

Although systemic inflammatory responses attributable to infection may lead to significant lung injury,the precise molecular mechanisms leading to lung damage are poorly understood and therapeutic options remain limited.Here,we show that myeloid monocyte chemotactic protein-inducible protein 1(MCPIP1)plays a central role in protecting against LPS-induced inflammation and lung injury.Myeloid-specific MCPIP1 knockout mice developed spontaneous inflammatory syndromes,but at a late age compared to global MCPIP1 knockout mice.Moreover,mice with a myeloid-specific deletion of MCPIP1 were extremely sensitive to LPS-induced lung injury due to overproduction of proinflammatory cytokines and chemokines.We identified C/EBPβand C/EBPδ,two critical transcriptional factors that drive cytokine production and lung injury,as targets of MCPIP1 RNase.LPS administration caused MCPIP1 protein degradation in the lungs.Pharmacological inhibition of MALT1,a paracaspase that cleaves MCPIP1,by MI-2 selectively increased the MCPIP1 protein levels in macrophages and in the lungs.Meanwhile,administration of MI-2 protected mice from LPS-induced inflammation,lung injury and death.Collectively,these results indicate that myeloid MCPIP1 is central in controlling LPS-induced inflammation and lung injury.Pharmacological inhibition of MALT1 protease activity may be a good strategy to treat inflammatory diseases by enhancing MCPIP1 expression in myeloid cells.