TLR5 agonist entolimod reduces the adverse toxicity of TNF while preserving its antitumor effects.

Tumor necrosis factor alpha (TNF) is capable of inducing regression of solid tumors. However, TNF released in response to Toll-like receptor 4 (TLR4) activation by bacterial lipopolysaccharide (LPS) is the key mediator of cytokine storm and septic shock that can cause severe tissue damage limiting a...

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Main Authors: Gary J Haderski, Bojidar M Kandar, Craig M Brackett, Ilia M Toshkov, Christopher P Johnson, Geraldine M Paszkiewicz, Venkatesh Natarajan, Anatoli S Gleiberman, Andrei V Gudkov, Lyudmila G Burdelya
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2020-01-01
Series:PLoS ONE
Online Access:https://doi.org/10.1371/journal.pone.0227940
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spelling doaj-aff8832bcd384418b01c7670ffe0eb0c2021-03-04T11:19:34ZengPublic Library of Science (PLoS)PLoS ONE1932-62032020-01-01152e022794010.1371/journal.pone.0227940TLR5 agonist entolimod reduces the adverse toxicity of TNF while preserving its antitumor effects.Gary J HaderskiBojidar M KandarCraig M BrackettIlia M ToshkovChristopher P JohnsonGeraldine M PaszkiewiczVenkatesh NatarajanAnatoli S GleibermanAndrei V GudkovLyudmila G BurdelyaTumor necrosis factor alpha (TNF) is capable of inducing regression of solid tumors. However, TNF released in response to Toll-like receptor 4 (TLR4) activation by bacterial lipopolysaccharide (LPS) is the key mediator of cytokine storm and septic shock that can cause severe tissue damage limiting anticancer applications of this cytokine. In our previous studies, we demonstrated that activation of another Toll-like receptor, TLR5, could protect from tissue damage caused by a variety of stresses including radiation, chemotherapy, Fas-activating antibody and ischemia-reperfusion. In this study, we tested whether entolimod could counteract TNF-induced toxicity in mouse models. We found that entolimod pretreatment effectively protects livers and lungs from LPS- and TNF-induced toxicity and prevents mortality caused by combining either of these agents with the sensitizer, D-galactosamine. While LPS and TNF induced significant activation of apoptotic caspase 3/7, lipid tissue peroxidation and serum ALT accumulation in mice without entolimod treatment, these indicators of toxicity were reduced by entolimod pretreatment to the levels of untreated control mice. Entolimod was effective when injected 0.5-48 hours prior to, but not when injected simultaneously or after LPS or TNF. Using chimeric mice with hematopoiesis differing in its TLR5 status from the rest of tissues, we showed that this protective activity was dependent on TLR5 expression by non-hematopoietic cells. Gene expression analysis identified multiple genes upregulated by entolimod in the liver and cultured hepatocytes as possible mediators of its protective activity. Entolimod did not interfere with the antitumor activity of TNF in mouse hepatocellular and colorectal tumor models. These results support further development of TLR5 agonists to increase tissue resistance to cytotoxic cytokines, reduce the risk of septic shock and enable safe systemic application of TNF as an anticancer therapy.https://doi.org/10.1371/journal.pone.0227940
collection DOAJ
language English
format Article
sources DOAJ
author Gary J Haderski
Bojidar M Kandar
Craig M Brackett
Ilia M Toshkov
Christopher P Johnson
Geraldine M Paszkiewicz
Venkatesh Natarajan
Anatoli S Gleiberman
Andrei V Gudkov
Lyudmila G Burdelya
spellingShingle Gary J Haderski
Bojidar M Kandar
Craig M Brackett
Ilia M Toshkov
Christopher P Johnson
Geraldine M Paszkiewicz
Venkatesh Natarajan
Anatoli S Gleiberman
Andrei V Gudkov
Lyudmila G Burdelya
TLR5 agonist entolimod reduces the adverse toxicity of TNF while preserving its antitumor effects.
PLoS ONE
author_facet Gary J Haderski
Bojidar M Kandar
Craig M Brackett
Ilia M Toshkov
Christopher P Johnson
Geraldine M Paszkiewicz
Venkatesh Natarajan
Anatoli S Gleiberman
Andrei V Gudkov
Lyudmila G Burdelya
author_sort Gary J Haderski
title TLR5 agonist entolimod reduces the adverse toxicity of TNF while preserving its antitumor effects.
title_short TLR5 agonist entolimod reduces the adverse toxicity of TNF while preserving its antitumor effects.
title_full TLR5 agonist entolimod reduces the adverse toxicity of TNF while preserving its antitumor effects.
title_fullStr TLR5 agonist entolimod reduces the adverse toxicity of TNF while preserving its antitumor effects.
title_full_unstemmed TLR5 agonist entolimod reduces the adverse toxicity of TNF while preserving its antitumor effects.
title_sort tlr5 agonist entolimod reduces the adverse toxicity of tnf while preserving its antitumor effects.
publisher Public Library of Science (PLoS)
series PLoS ONE
issn 1932-6203
publishDate 2020-01-01
description Tumor necrosis factor alpha (TNF) is capable of inducing regression of solid tumors. However, TNF released in response to Toll-like receptor 4 (TLR4) activation by bacterial lipopolysaccharide (LPS) is the key mediator of cytokine storm and septic shock that can cause severe tissue damage limiting anticancer applications of this cytokine. In our previous studies, we demonstrated that activation of another Toll-like receptor, TLR5, could protect from tissue damage caused by a variety of stresses including radiation, chemotherapy, Fas-activating antibody and ischemia-reperfusion. In this study, we tested whether entolimod could counteract TNF-induced toxicity in mouse models. We found that entolimod pretreatment effectively protects livers and lungs from LPS- and TNF-induced toxicity and prevents mortality caused by combining either of these agents with the sensitizer, D-galactosamine. While LPS and TNF induced significant activation of apoptotic caspase 3/7, lipid tissue peroxidation and serum ALT accumulation in mice without entolimod treatment, these indicators of toxicity were reduced by entolimod pretreatment to the levels of untreated control mice. Entolimod was effective when injected 0.5-48 hours prior to, but not when injected simultaneously or after LPS or TNF. Using chimeric mice with hematopoiesis differing in its TLR5 status from the rest of tissues, we showed that this protective activity was dependent on TLR5 expression by non-hematopoietic cells. Gene expression analysis identified multiple genes upregulated by entolimod in the liver and cultured hepatocytes as possible mediators of its protective activity. Entolimod did not interfere with the antitumor activity of TNF in mouse hepatocellular and colorectal tumor models. These results support further development of TLR5 agonists to increase tissue resistance to cytotoxic cytokines, reduce the risk of septic shock and enable safe systemic application of TNF as an anticancer therapy.
url https://doi.org/10.1371/journal.pone.0227940
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