The anti-inflammatory effects of heat shock protein 72 involve inhibition of high-mobility-group box 1 release and proinflammatory function in macrophages.
High-mobility-group box 1 (HMGB1), a nuclear protein, has recently been identified as an important mediator of local and systemic inflammatory diseases when released into the extracellular milieu. Anti-inflammatory regulation by the stress response is an effective autoprotective mechanism when the host encounters harmful stimuli, but the mechanism of action remains incompletely delineated. In this study, we demonstrate that increases in levels of a major stress-inducible protein, heat shock protein 72 (Hsp72) by gene transfection attenuated LPS- or TNF-alpha-induced HMGB1 cytoplasmic translocation and release. The mechanisms involved inhibition of the chromosome region maintenance 1 (CRM1)-dependent nuclear export pathway. Overexpression of Hsp72 inhibited CRM1 translocation and interaction between HMGB1 and CRM1 in macrophages post-LPS and TNF-alpha treatment. In addition, overexpression of Hsp72 strongly inhibited HMGB1-induced cytokine (TNF-alpha, IL-1beta) expression and release, which correlated closely with: 1) inhibition of the MAP kinases (p38, JNK, and ERK); and 2) inhibition of the NF-kappaB pathway. Taken together, these experiments suggest that the anti-inflammatory activity of Hsp72 is achieved by interfering with both the release and proinflammatory function of HMGB1. Our experimental data provide important insights into the anti-inflammatory mechanisms of heat shock protein protection.
Tang
Daolin
D
Laboratory of Shock, Department of Pathophysiology, Xiangya School of Medicine, Changsha, People's Republic of China.
Kang
Rui
R
Xiao
Weimin
W
Wang
Haichao
H
Calderwood
Stuart K
SK
Xiao
Xianzhong
X
D000818:Animals; D015153:Blotting, Western; D024202:Electrophoretic Mobility Shift Assay; D024243:HMGB1 Protein / Q000378:metabolism*; D050884:HSP72 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007249:Inflammation / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D028884:Karyopherins / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000097606:Exportin 1 Protein
D024243:HMGB1 Protein; D050884:HSP72 Heat-Shock Proteins; D053583:Interleukin-1beta; D028884:Karyopherins; D008070:Lipopolysaccharides; D020929:Mitogen-Activated Protein Kinase Kinases; D016328:NF-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D000097606:Exportin 1 Protein