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The inhibition of LPS-induced production of inflammatory cytokines by HSP70 involves inactivation of the NF-kappaB pathway but not the MAPK pathways.
- Source :
-
Shock (Augusta, Ga.) [Shock] 2006 Sep; Vol. 26 (3), pp. 277-84. - Publication Year :
- 2006
-
Abstract
- The objective of this study was to evaluate the negative regulatory role of heat shock protein 70 (HSP70) on endotoxin-induced activation of inflammatory cytokine signaling pathways in a macrophage cell line. Our studies show that elevation of HSP70 either by activation of the heat shock response (HSR) or through forced expression of the hsp70.1 gene downregulates cytokine expression. Our experiments showed that activation of the HSR and HSP70 overexpression could inhibit LPS-mediated expression of the proinflammatory cytokines TNF-alpha and IL-1 at the mRNA and protein levels. We also investigated the effects of HSP70 elevation on signaling pathways downstream of LPS and its receptors, including the NF-kappaB and mitogen-activated protein kinase (MAPK) pathways. The effects of HSP70 on cytokine expression were correlated with its effects on activation of NF-kappaB, a known activator of the tnfalpha and Il-1 genes. Overexpression of HSP70 inhibited the nuclear translocation of p65, the transcriptionally active component of the NF-kappaB complex, and prevented the degradation of IkappaBalpha, the regulator of NF-kappaB activity. However, HSP70 elevation did not markedly inhibit signaling through the MAPK arm of the LPS-induced pathway, suggesting that the effects of HSP70 are mediated primarily through the NF-kappaB cascade. Our experiments therefore suggested that elevated levels of HSP70 inhibit LPS-induced production of inflammatory cytokines by a mechanisms involving inactivation of NF-kappaB but cast doubt on significant role for the MAPK pathway in these effects.
- Subjects :
- Active Transport, Cell Nucleus drug effects
Animals
Cell Line, Tumor
Cell Nucleus metabolism
Cytokines genetics
Gene Expression drug effects
Gene Expression genetics
Heat-Shock Response physiology
Humans
I-kappa B Proteins metabolism
Interleukin-1 genetics
Interleukin-1 metabolism
Macrophages drug effects
Macrophages metabolism
Mice
Mice, Inbred BALB C
Mitogen-Activated Protein Kinases metabolism
NF-KappaB Inhibitor alpha
Phosphoric Monoester Hydrolases metabolism
Phosphorylation drug effects
Transcription Factor RelA metabolism
Transfection
Tumor Necrosis Factor-alpha genetics
Tumor Necrosis Factor-alpha metabolism
Cytokines metabolism
HSP70 Heat-Shock Proteins physiology
Lipopolysaccharides pharmacology
MAP Kinase Signaling System physiology
NF-kappa B metabolism
Signal Transduction physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1073-2322
- Volume :
- 26
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Shock (Augusta, Ga.)
- Publication Type :
- Academic Journal
- Accession number :
- 16912653
- Full Text :
- https://doi.org/10.1097/01.shk.0000223134.17877.ad