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Resveratrol Downregulates Biomarkers of Sepsis Via Inhibition of Proteasome's Proteases

Silswal, Neerupma*; Reddy, Nidhi S.; Qureshi, Asaf A.*; Qureshi, Nilofer*,†

doi: 10.1097/SHK.0000000000001080
Basic Science Aspects
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ABSTRACT Lipopolysaccharide (LPS) is the main agonist of gram-negative bacteria and initiates inflammation. We recently reported that plasmas from sepsis patients revealed increased levels of following group of biomarkers; VCAM-1, ICAM1, CRP, resistin, and proteasome LMP subunits. Our objective here was to compare effects of resveratrol (shown to be a nonspecific proteasome inhibitor by us) and a known LMP7 inhibitor (ONX-0914, specific inhibitor) on proteasome's activities, as well as on inflammatory markers mentioned above in human blood monocytes. Using fluorescence-based assays on blood monocytes purified proteasomes, resveratrol (0–100 μM) inhibited all three protease activities, predominantly LMP7. Similarly, resveratrol inhibited all three protease activities using cell-based luminescence assay. In contrast, ONX-0914 was more selective and potent for LMP7 activity. Resveratrol and ONX-0914, both significantly inhibited expression of LPS-induced biomarkers mentioned above in CD14+ monocytes. Moreover, resveratrol itself, as well as in combination with LPS, accumulated pIκBα in CD14+ monocytes. Collectively, our data suggest that resveratrol is a less potent inhibitor of all three; CT-like (predominantly LMP7), T-like and PA protease activities and is less toxic to human monocytes than ONX-0914 (a selector inhibitor of only LMP7) as observed by an autophagy detection kit. Also, resveratrol reduces LPS-induced inflammatory cytokine expression by decreasing the translocation of NF-κB due to an increase in inhibitor pIκBα. Therefore, resveratrol can be used to curb inflammation in diseased states like sepsis and other disorders.

*Shock/Trauma Research Center, Department of Basic Medical Science, School of Medicine, University of Missouri Kansas City, Kansas City, Missouri

Departments of Pharmacology and Toxicology, School of Pharmacy, University of Missouri Kansas City, Kansas City, Missouri

Address reprint requests to Nilofer Qureshi, PhD, Department of Basic Medical Science, School of Medicine, Shock/Trauma Research Center, 2411 Holmes Street, University of Missouri Kansas City, Kansas City, MO 64108. E-mail: qureshin@umkc.edu

Received 7 June, 2017

Revised 23 June, 2017

Accepted 4 December, 2017

This study was supported in part by NIH grants GM102631 (NQ) and GM102631S1 (NQ).

The authors have no financial conflicts of interest.

© 2018 by the Shock Society