Steroid responses in sepsis: some novel thinking that may provide new insight
© BioMed Central Ltd 2013
Published: 27 June 2013
Glucocorticoid use in sepsis is controversial. In contrast to other extracellular signaling molecules, glucocorticoid receptors (GRs) are intra-cytoplasmic. Several GR isoforms have been identified. A study in Critical Care Forum suggests that sepsis alters the abundance of the dominant negative GRβ. Here we discuss GR isoforms and how they may affect cellular responses to glucocorticoids in sepsis.
The use of glucocorticoids in the management of patients with sepsis remains controversial. In this issue of Critical Care Forum, Guerrero and colleagues  present findings that may bring some clarity to the topic.
The dispute regarding steroid use in sepsis touches on the most basic aspects of glucocorticoid action. Trials performed in the 1970s and 1980s indicated that pharmacologic doses were harmful , and glucocorticoid use was abandoned, only to resurface with the seminal article by Annane and colleagues  in 2002. These data suggested that glucocorticoids would be of value in septic patients incapable of mounting a sufficient endogenous response (that is, in patients with relative adrenal insufficiency). The work by Annane and colleagues was followed by the CORTICUS (Cortico-steroid Therapy of Septic Shock) trial , the data of which did not confirm the findings of Annane and colleagues. However, significant methodological differences between the two studies leave the issue unresolved. To this day, the debate continues.
In the discrepant results of these trials, two specific findings in patients with sepsis are of particular importance. First, glucocorticoids induce polar opposite responses in different tissues. Steroids limit activity in white blood cells and thus function as anti-inflammatory agents. But in the liver and heart, glucocorticoids stimulate reactions that are pro-inflammatory: expression of genes encoding acute-phase reactants and potentiation of the cardio-stimulatory actions of catecholamines. The second key finding relates to serum levels, which are often quite elevated, a finding that may reflect changes in cortisol metabolism induced by critical illness . Given these issues, it is not surprising that the role of glucocorticoids in sepsis is confounding.
In contrast to the isoforms of GRα, GRβ does not bind glucocorticoids. By means of mechanisms that are unclear, GRβ acts as a dominant negative inhibitor of glucocorticoid-responsive gene expression. Guerrero and colleagues found that the expression of GRβ in white blood cells of nine patients with septic shock was significantly higher on admission than on discharge. Serum from these patients enhanced the in vitro expression of both GRα and GRβ in cultured T and B cells but had a more profound effect on GRβ. The serum also induced glucocorticoid resistance in mononuclear cells in vitro. These findings suggest that septic shock inhibits the activity of glucocorticoids by enhancing expression of the dominant negative GRβ.
Variability in the abundance of GRβ might explain why exogenous glucocorticoids exert such capricious effects in patients with sepsis. Enhanced GRβ expression might also explain why glucocorticoid levels are so dramatically elevated in patients with sepsis: the presence of a receptor that inhibits glucocorticoid activity will induce increased release of the hormone to compensate for and stimulate the desired response. We have invoked a similar explanation for the markedly increased interleukin-6 (IL-6) levels observed in sepsis. Our work on IL-6 has demonstrated impairment of the GP130/JAKS1/STAT-3 signal transduction pathway that mediates many of that cytokine's effects . To overcome this block, increasingly massive amounts of IL-6 are produced and released. The implication of these findings may be that the increased abundance of glucocorticoids, IL-6, and perhaps a number of additional mediators and hormones is an adaptive response that should be augmented. However, most trials of cytokine-based therapy attempt exactly the opposite: blocking activity. Perhaps it is time to reconsider the hypothesis underlying these interventions. Certainly, the findings of Guerrero and colleagues reinforce the notion that sepsis is a complex disorder and mono-therapy is unlikely to work.
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