SP Ribeiro, J Villar, GP Downey, JD Edelson and AS Slutsky
Department of Medicine, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.

We have previously demonstrated that induction of the stress response, by heat stress or sodium arsenite, administered 18 h before initiation of sepsis in rats, significantly decreased mortality and lung injury. As a possible mechanism underlying this effect, we hypothesized that the induction of the stress response, prior to bacterial endotoxin (lipopolysaccharide, LPS) stimulation, would cause a decrease in synthesis and/or release of tumor necrosis factor-alpha (TNF-alpha), making the animals more resistant to sepsis. Rats exposed to Salmonella typhosa LPS demonstrated a rise in plasma TNF-alpha. In contrast, rats exposed to heat stress or to sodium arsenite 18 h prior to LPS had significantly lower levels of plasma TNF-alpha. To examine the mechanisms by which the stress response mediates this decrease, we studied cultured alveolar macrophages. Similar to in vivo studies, TNF released into supernatants of alveolar macrophages treated with LPS was significantly higher than from cells exposed to the stress response prior to LPS. The decrease in TNF-alpha protein release was not accompanied by a similar decrease in TNF-alpha mRNA levels or by a decrease in cell-associated TNF-alpha, suggesting possible posttranslational regulation of TNF-alpha. To determine whether the decrease in TNF-alpha release was due to binding and sequestration by heat shock proteins (HSP), TNF-alpha was purified by immunoprecipitation. Under these conditions, TNF-alpha and HSP72kDa coprecipitated from cells that had received stress treatment prior to LPS. These data implicate HSP in posttranslational control of TNF-alpha release in LPS-stimulated alveolar macrophages exposed to the stress response.

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