New Insights into the Role of Glutathione in the Mechanism of Fever

Abstract

Glutathione is one of the most important and potent antioxidants. The development of pharmacological compounds that can either increase or decrease glutathione concentrations has allowed investigation into the role of glutathione in various biological processes, including immune responses. Recent findings have shown that glutathione not only affects certain factors involved in immunological processes but also modifies complex immune reactions such as fever. Until recently, it was not known why some patients do not develop fever during infection. Data suggest that fever induction is associated with oxidative stress; therefore, antioxidants such as glutathione can reduce pyrexia. Surprisingly, new studies have shown that low glutathione levels can also inhibit fever. In this review, we focus on recent advances in this area, with an emphasis on the role of glutathione in immune responses accompanied by fever. We describe evidence showing that disturbed glutathione homeostasis may be responsible for the lack of fever during infections. We also discuss the biological significance of the antipyretic effects produced by pharmacological glutathione modulators.

Keywords: antioxidants; fever; glutathione modulators; immunity; inflammation; oxidative stress.

Figure 1

The mechanism of fever. Lipopolysaccharide (LPS) released from bacteria is recognized by Toll-like receptor 4 (TLR4). It provides signal transmission through TRAF6 and IKK family kinases to induce NF-κB-dependent gene expression, resulting in the release of pyrogenic tumor necrosis factor α (TNFα), interleukin (IL)1-β and IL-6. TLR4 activation also triggers the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) to diacylglycerol (DAG) and inositol trisphosphate (IP3) by phospholipase C (PLC). Diacylglycerol lipase (DAGL) hydrolyses diacylglycerol (DAG) presented in membrane releasing free arachidonic acid (AA). Additionally, IP3 stimulates calcium liberation from the endoplasmic reticulum to the cytoplasm, which, in turn, drives the activation of phospholipase A2 (PLA2) to release arachidonic acid from membrane phospholipids. AA is then metabolized by cyclooxygenase (COX-2) to prostaglandin H2 (PGH2). Subsequently, microsomal prostaglandin E2 synthase (mPGES-1) converts PGH2 to prostaglandin E2 (PGE2), a major mediator of fever.

Figure 2

Glutathione synthesis. Three essential amino acids—glutamate, cysteine, and glycine—combine to form the tripeptide glutathione (GSH). At the beginning, cysteine is joined to glutamate through the action of glutamate cysteine ligase (GCL) to produce γ-glutamylcysteine, which proceeds to link with glycine via glutathione synthase (GS) action.

Figure 3

Glutathione exists in both the thiol-reduced (GSH) form and the disulfide-oxidized (GSSG) form. GSH:GSSG recycling is catalyzed by GSH peroxidase (GP) and GSH reductase (GR).

Figure 4

The effect of glutathione (GSH) and its modulators on the mechanism of fever. Detailed description of the fever mechanism is presented in Figure 1. The influence of glutathione and its modulators is depicted by double arrowheads and green color (stimulation) or blunt ends and red color (inhibition). N-acetyl-l-cysteine (NAC)—glutathione precursor; buthionine sulfoximine (BSO) and phorone—glutathione depletors.