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Heat Shock Inhibition of Lipopolysaccharide-Mediated Tumor Necrosis Factor Expression Is Associated With Nuclear Induction of MKP-1 and Inhibition of Mitogen-Activated Protein Kinase Activation

Heat Shock Inhibition of Lipopolysaccharide-Mediated Tumor Necrosis Factor Expression Is Associated With Nuclear Induction of MKP-1 and Inhibition of Mitogen-Activated Protein Kinase Activation

Lauren Sanlorenzo, Bin Zhao, Donn Spight, Alvin G Denenberg, Kristen Page, Hector R Wong, Thomas P Shanley

Crit Care Med. 2004 Nov;32(11):2284-92.

PMID: 15640643

Abstract:

Objective:
Application of heat shock before an inflammatory stimulus often results in an attenuated response to that stimulus. As a result, it has become increasingly appreciated that heat shock may induce cross-tolerance to a variety of stimuli based on in vitro and in vivo models. Circulating peripheral blood monocytes are key mediators of cytokine release following endotoxin challenge. The mitogen-activated protein kinases play a key role in the transcriptional regulation of this response including expression of tumor necrosis factor. As such, counterregulatory phosphatases that target mitogen-activated protein kinase may play a role in this heat shock-mediated effect. We hypothesized that prior heat shock to monocytes would induce a phosphatase, MKP-1, that regulated mitogen-activated protein kinase activity and subsequently conferred cross-tolerance to lipopolysaccharide stimulation.
Design:
Experimental.
Setting:
University research foundation laboratory.
Subjects:
THP-1 human monocyte cell line.
Interventions:
THP-1 cells were exposed to either heat shock (43 degrees C, 1 hr) or normothermia (37 degrees C, 1 hr) and allowed to recover before stimulation with endotoxin (lipopolysaccharide).
Measurements and main results:
Induction of a heat shock response was determined by heat shock protein-70 expression. Tumor necrosis factor and interleukin-10 were measured by enzyme-linked immunosorbent assay to assess heat shock inhibition of lipopolysaccharide-induced gene expression. The effect of heat shock on lipopolysaccharide-mediated activation of the p38 and ERK kinases was examined by measuring phospho-specific isoforms of p38 and ERK1/2 and correlated to in vitro kinase activity. Confirmatory data were generated from experiments employing either pharmacologic inhibition or genetic deletion of MKP-1. Heat shock induced the nuclear localized phosphatase, MKP-1, that attenuated p38 and ERK kinase activity resulting in significantly diminished tumor necrosis factor expression in response to lipopolysaccharide.
Conclusions:
The effect of heat shock on decreasing the tumor necrosis factor response to lipopolysaccharide is conferred by induction of MKP-1, which negatively regulates p38 and ERK kinases. Modulation of phosphatase activity may be a potential strategy for attenuating acute inflammatory responses.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4241052	Heat Shock Factor 1 human			Price

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