期刊
CYTOKINE
卷 113, 期 -, 页码 427-432出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.cyto.2018.10.020
关键词
Hsp90 inhibitors; P53; Inflammation; Acute Lung Injury
资金
- College of Pharmacy, University of Louisiana Monroe, Monroe, LA [5RSPEC 300010 271008, 5CALHN-260615]
- Malcolm Feist Partners Across Campuses Seed Program, Center for Cardiovascular Diseases and Sciences, Louisiana State University Health Shreveport, Shreveport, LA [BRS005]
- Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health [5 P20 GM103424-15, 3 P20 GM103424-15S1]
- NHLBI [P01-HL101902]
P53 has been recently involved in the defense against inflammation. The guardian of the genome appears to orchestrate cellular responses against bacterial toxins, by regulating crucial pathways that orchestrate the vascular barrier functions. Indeed, an emerging body of evidence suggests that this tumor suppressor is involved in the mediation of the beneficial effects of Hsp90 inhibition in the inflamed endothelium. Interestingly, those compounds augment the abundance of P53 in the intracellular niche, while LPS dramatically reduces it. The current study focuses on the outcome of LPS and Hsp90 inhibition on P53 phosphorylation, since this modification negatively affects P53 stability. In an in vitro model of LPS - induced vascular leak in bovine pulmonary arterial endothelial cells, LPS induced P53 phosphorylation in four distinct residues, namely Ser. 6, Ser. 15, Ser. 33 and Ser. 392. Furthermore, LPS triggered the activation of the myosin light chain 2, which produces endothelial barrier dysfunction by cellular retraction and intercellular gap formation. Indeed, mice exposed to the toxin demonstrated elevated levels of the pro - inflammatory cytokines IL-2 and IL-10 in the bronchoalveolar lavage fluid. In bold contrast, the HSP90 inhibitor 17-DMAG, counteracted the LPS - induced effects both in vivo and in vitro. Specifically, this hsp90 inhibitor reduced phosphorylated P53 levels and lessened the activation of myosin light chain 2 (phosphorylation) in the bovine endothelium. Moreover, 17 - DMAG suppressed inflammation in mouse lungs, as reflected in reduced IL-2 and IL-10 BALF levels. In summary, the present results support previous observations on the protective role of P53 against inflammation and clarify mechanisms that govern vascular barrier function.
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