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°C, 1 hr) or normothermia (37°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.
Original language | English (US) |
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Pages (from-to) | 2284-2292 |
Number of pages | 9 |
Journal | Critical care medicine |
Volume | 32 |
Issue number | 11 |
DOIs | |
State | Published - Nov 2004 |
Externally published | Yes |
Keywords
- ERK
- Heat shock
- MKP-1
- Mitogen-activated protein kinases
- Phosphatases
- Tumor necrosis factor
- p38
ASJC Scopus subject areas
- Critical Care and Intensive Care Medicine