Evaluation of HSP70 deficiency in the inflammatory response in vivo and in vitro: The impact of HSP90 expression, glucocorticoid release, and glutamine administration

Abstract

The present study aimed to explore the pathway through which Heat Shock Protein 70 (HSP70) is involved in inflammation and sepsis and the possible interaction with glutamine, an essential nutrient during sepsis. We also evaluated the possible interaction of HSP70 with HSP90, another HSP involved in sepsis. Therefore, we utilized mice with specific deletion of the Hsp70.1 and Hsp70.3 genes (Hsp70-/-) and their wild type littermates (Hsp70+/+) for the in vivo studies and primary macrophages collected from Hsp70+/+ and Hsp70-/- mice for the in vitro studies. We found that HSP70 deficiency was associated with lower inflammatory cytokine levels in plasma and lung tissue and increased levels of glucocorticoid secretion during inflammation in vivo. On the contrary, Hsp70-/- murine peritoneal macrophages showed increased inflammatory response compared to Hsp70+/+ macrophages, following LPS stimulation. Glutamine administration repressed the in vivo secretion of plasma cytokines from Hsp70-/- mice while enhanced the in vitro secretion of cytokines from macrophages of the same genotype (Hsp70-/-), but it did not affect the secretion of cytokines from wild type mice either in vivo or in vitro, following LPS treatment. Our data also demonstrated that HSP70 deficiency was associated with increased glucocorticoid release, in vivo. In vitro, pre-treatment of macrophages from both genotypes with HSP90 inhibitor significantly attenuated IL-6 secretion only from Hsp70-/- cells, following LPS treatment. In summary, in vivo, the lack of HSP70 leads to an anti-inflammatory phenotype, while in vitro, the lack of HSP70 in macrophages gives rise to a proinflammatory phenotype, which may be mediated by the HSP90. Both in vivo and in vitro, glutamine treatment responses in Hsp70-/- mice suggest alternative pathways bypassing HSP70.

Keywords

• hsp70
• glutamine
• cytokines
• corticosterone
• hsp90
• inflammation