Glutamine May Repress the Weak LPS and Enhance the Strong Heat Shock Induction of Monocyte and Lymphocyte HSP72 Proteins but May Not Modulate the HSP72 mRNA in Patients with Sepsis or Trauma

Abstract

Objective. We assessed the lipopolysaccharide (LPS) or heat shock (HS) induction of heat shock protein-72 (HSP72) in peripheral blood mononuclear cells (PBMCs) of patients with severe sepsis (SS) or trauma-related systemic inflammatory response syndrome (SIRS), compared to healthy individuals (H); we also investigated any pre- or posttreatment modulating glutamine (Gln) effect. Methods. SS (11), SIRS (10), and H (19) PBMCs were incubated with 1 μg/mL LPS or 43°HS. Gln 10 mM was either added 1 h before or 1 h after induction or was not added at all. We measured monocyte (m), lymphocyte (l), mRNA HSP72, HSP72 polymorphisms, interleukins (ILs), monocyte chemoattractant protein-1 (MCP-1), and cortisol levels. Results. Baseline lHSP72 was higher in SS (p < 0.03), and mHSP72 in SIRS (p < 0.02), compared to H. Only HS induced l/mHSP72/mRNA HSP72; LPS induced IL-6, IL-8, IL-10, and MCP-1. Induced mRNA was related to l/mHSP72, and was related negatively to cytokines. Intracellular l/mHSP72/HSP72 mRNA was related to serum ILs, not being influenced by cortisol, illness severity, and HSP72 polymorphisms. Gln did not induce mRNA in any group but modified l/mHSP72 after LPS/HS induction unpredictably. Conclusions. HSP72 mRNA and l/mHSP72 are higher among critically ill patients, further induced by HS, not by LPS. HSP72 proteins and HSP72 mRNA are related to serum ILs and are negatively related to supernatant cytokines, not being influenced by HSP72 polymorphisms, cortisol, or illness severity. Gln may depress l/mHSP72 after LPS exposure and enhance them after HS induction, but it may not affect early induced HSP72 mRNA.

Increased glucocorticoid receptor expression in sepsis is related to heat shock proteins, cytokines, and cortisol and is associated with increased mortality

“…Although a negative correlation between hyperthermia and the number of receptors has been previously suggested [ 30 ], we could not find any relation between hGRα and temperature, lactate, glucose, LDH, IL-17, or PCT. In vitro, only heat shock induced mHSP72 and HSP72 mRNA but not lipopolysaccharide [ 31 ]. Our findings are in agreement with those of a recent study showing that in sepsis extracellular HSP72 and HSP90α are increased, while intracellular HSPs are repressed [ 32 ].…”

Glucocorticoid receptor activation is associated with increased resistance to heat‐induced hyperthermia and injury

“…On the other hand, released GR is known to transcriptionally upregulate anti‐inflammatory cytokines and suppress pro‐inflammatory cytokines. It has been shown that both GR and HSPs are significantly elevated in the leucocytes of patients with severe sepsis …”

“…One notable example is the difference between animal and human studies regarding the protective effects of intracellular HSP72 against acute stress. Experimental studies have consistently shown a strong molecular, biological and clinical protective effect for HSP72 in sepsis, but clinical studies are inconclusive, varying from a protective in vitro effect to an in vivo HSP72‐mortality association …”

Effects of prophylactic administration of glutamine on CD4+T cell polarisation and kidney injury in mice with polymicrobial sepsis

“…However, an ex vivo study showed that high-dose GLN did not induce Th1/Th2/Th17 cytokine responses in peripheral blood mononuclear cells (PBMC) obtained from patients with severe sepsis (18) . Also, GLN administration may repress heat shock protein 72 (HSP72) expression of PBMC after lipopolysaccharide exposure and enhance HSP72 proteins after heat shock induction in patients with sepsis (19) . The influence of GLN on T cell regulation and subsequent outcome in sepsis remain inconsistent.…”