LPS-induced cytokine levels are repressed by elevated expression of HSP70 in rats: possible role of NF-kappaB

TY - JOUR

T1 - LPS-induced cytokine levels are repressed by elevated expression of HSP70 in rats

T2 - possible role of NF-kappaB

AU - Dokladny, Karol

AU - Lobb, Rebecca

AU - Wharton, Walker

AU - Ma, Thomas Y

AU - Moseley, Pope L

PY - 2010/3

Y1 - 2010/3

N2 - Heat shock protein (HSP)70 provides a spectrum of protection against any of a variety of stresses, preventing damage measured at the level of molecules, cells, as well as whole organism. We have previously reported that lipopolysaccharide (LPS)-induced lethality in rats is prevented by a previous exposure to a mild thermal stress and that a thermal stress sufficient to induce HSP70 expression in the liver is accompanied by an inhibition of endotoxinmediated cytokines and modulation of febrile response. However, the effect of HSP70 upregulation on cytokine expression in animals is unknown. The aim of the present study was to demonstrate the effect of HSP70 overexpression with adenovirus administration on LPSinduced increase in cytokines levels in animals. In the present study, Sprague-Dawley rats were infected, with either the control AdTrack or Ad70 virus that directs the expression of human HSP70. After a 5-day incubation, animals were injected with either saline alone or LPS (50 μg/kg). Four hours later, blood samples were drawn and plasma levels of interleukin (IL)-6 or tumor necrosis factor (TNF)-α were measured by enzyme-linked immunosorbent assay. Our data demonstrate for the first time that HSP70 overexpression with adenovirus injection prevented the LPS-induced increase in TNF-α and IL-6 levels in rats. Repression, of LPS-induced cytokines expressions by HSP70 upregulation was associated with inhibited IKBa degradation and nuclear factor kappa-B (NF-κB) p65 nuclear translocation in liver, suggesting that HSP70 over expression may regulate LPS-induced cytokines expression through NF-κB pathway. We conclude that the effects of heat stress-induced increase in HSP70 protein expression on LPS-induced cytokine elaboration in whole animals can be reproduced by the actions of a single gene product.

AB - Heat shock protein (HSP)70 provides a spectrum of protection against any of a variety of stresses, preventing damage measured at the level of molecules, cells, as well as whole organism. We have previously reported that lipopolysaccharide (LPS)-induced lethality in rats is prevented by a previous exposure to a mild thermal stress and that a thermal stress sufficient to induce HSP70 expression in the liver is accompanied by an inhibition of endotoxinmediated cytokines and modulation of febrile response. However, the effect of HSP70 upregulation on cytokine expression in animals is unknown. The aim of the present study was to demonstrate the effect of HSP70 overexpression with adenovirus administration on LPSinduced increase in cytokines levels in animals. In the present study, Sprague-Dawley rats were infected, with either the control AdTrack or Ad70 virus that directs the expression of human HSP70. After a 5-day incubation, animals were injected with either saline alone or LPS (50 μg/kg). Four hours later, blood samples were drawn and plasma levels of interleukin (IL)-6 or tumor necrosis factor (TNF)-α were measured by enzyme-linked immunosorbent assay. Our data demonstrate for the first time that HSP70 overexpression with adenovirus injection prevented the LPS-induced increase in TNF-α and IL-6 levels in rats. Repression, of LPS-induced cytokines expressions by HSP70 upregulation was associated with inhibited IKBa degradation and nuclear factor kappa-B (NF-κB) p65 nuclear translocation in liver, suggesting that HSP70 over expression may regulate LPS-induced cytokines expression through NF-κB pathway. We conclude that the effects of heat stress-induced increase in HSP70 protein expression on LPS-induced cytokine elaboration in whole animals can be reproduced by the actions of a single gene product.

KW - Adenoviridae Infections/blood

KW - Animals

KW - Body Weight

KW - Cell Line

KW - DNA-Binding Proteins/metabolism

KW - HSC70 Heat-Shock Proteins/metabolism

KW - Heat Shock Transcription Factors

KW - Humans

KW - Interleukin-6/blood

KW - Lipopolysaccharides/immunology

KW - Mice

KW - Protein Transport

KW - Rats

KW - Rats, Sprague-Dawley

KW - Transcription Factor RelA/metabolism

KW - Transcription Factors/metabolism

KW - Tumor Necrosis Factor-alpha/blood

U2 - 10.1007/s12192-009-0129-6

DO - 10.1007/s12192-009-0129-6

M3 - Journal article

C2 - 19551494

SN - 1355-8145

VL - 15

SP - 153

EP - 163

JO - Cell Stress and Chaperones

JF - Cell Stress and Chaperones

IS - 2

ER -