Heat shock protein 70 negatively regulates the heat-shock-induced suppression of the IkappaB/NF-kappaB cascade by facilitating IkappaB kinase renaturation and blocking its further denaturation.
Heat shock (HS) treatment has been previously shown to suppress the IkappaB/nuclear factor-kappaB (NF-kappaB) cascade by denaturing, and thus inactivating IkappaB kinase (IKK). HS is characterized by the induction of a group of heat shock proteins (HSPs). However, their role in the HS-induced suppression of the IkappaB/NF-kappaB cascade is unclear. Adenovirus-mediated HSP70 overexpression was found not to suppress the TNF-alpha-induced activation of the IkappaB/NF-kappaB pathway, thus suggesting that HSP70 is unlikely to suppress this pathway. When TNF-alpha-induced activation of the IkappaB/NF-kappaB pathway was regained 24 h after HS, HSP70 was found to be highly up-regulated. Moreover, blocking HSP70 induction delayed TNF-alpha-induced IkappaBalpha degradation and the resolubilization of IKK. In addition, HSP70 associated physically with IKK, suggesting that HSP70 is involved in the recovery process via molecular chaperone effect. Adenovirus-mediated HSP70 overexpression prior to HS blocked the IkappaBalpha stabilizing effect of HS by suppressing IKK insolubilization. Moreover, the up-regulation of endogenous HSP70 by preheating, suppressed this subsequent HS-induced IKK insolubilization, and this effect was abrogated by blocking HSP70 induction. These findings indicate that HSP70 accumulates during HS and negatively regulates the HS-induced suppression of the IkappaB/NF-kappaB cascade by facilitating the renaturation of IKK and blocking its further denaturation.
Lee
Kyoung-Hee
KH
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
Lee
Choon-Taek
CT
Kim
Young Whan
YW
Han
Sung Koo
SK
Shim
Young-Soo
YS
Yoo
Chul-Gyu
CG
D000256:Adenoviridae / Q000235:genetics; D015153:Blotting, Western; D001980:Bronchi / Q000166:cytology; D018929:Cell Culture Techniques; D002460:Cell Line; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis / Q000378:metabolism; D018869:Heat-Shock Response / Q000187:drug effects / Q000235:genetics*; D006358:Hot Temperature; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D020673:Protein Renaturation; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D013997:Time Factors; D014161:Transduction, Genetic; D015854:Up-Regulation
D018840:HSP70 Heat-Shock Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; D011994:Recombinant Proteins