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A5737 - Trim21 Inhibits Human Lung Microvascular Endothelial Cell Inflammatory Responses Through Attenuation of NF-kB Pathway and Intercellular Adhesion Molecules Expression
Author Block: L. Li1, P. R. Fleisher1, J. Wei1, B. Wang1, M. J. Kaltreider1, S. Li1, P. Sundd2, J. Zhao1; 1Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA, United States, 2Medicine-VMI, University of Pittsburgh, Pittsburgh, PA, United States.
Background: Vascular endothelium lines the entire circulation system and maintains vessel integrity. Endothelial cell (EC) inflammation is an important pathogenic feature of many inflammatory diseases such as acute lung injury and sepsis. Increase in EC inflammation results in neutrophil infiltration from the blood to the site of inflammation, further promoting EC permeability. Ubiquitin E3 ligase Trim21 has been known to be implicated in human disorders; however, the role of Trim21 in EC inflammation has not been reported. Here, we show that Trim21 exhibits an anti-inflammatory property in lung microvascular cells.
Methods and Results: Human lung microvascular cells (HLMVECs) were treated with IL-1β, TNFα, or lipopolysaccharide (LPS) for 2-9 h, and then Trim21 levels were determined by Western blotting. We found that Trim21 levels were reduced in response to these inflammatory stimuli. Further, HLMVECs were transfected with plasmids coding V5 tagged-Trim21, and then cells were treated with LPS for 6 h. LPS treatment significantly increased expression of intercellular adhesion molecule-1 (ICAM1) and vascular adhesion molecule-1 (VCAM1), while the effects were attenuated in Trim21-V5-overexpressing cells. NF-κB pathway plays a critical role in ICAM1 and VCAM1 expression. We found that LPS-induced phosphorylation of I-κB was diminished by overexpression of Trim21-V5.
Conclusions and future studies: Our findings discover an anti-inflammatory role of Trim21 in lung endothelial cells. This study suggests that reduction of Trim21 may contribute to vascular inflammation. Future study will focus on the molecular regulation of NF-κB by Trim21 and role of Trim21 in neutrophil adhesion to lung microvascular cells.