Interplay of the Inflammatory and Stress Systems in a Hepatic Cell Line: Interactions between Glucocorticoid Receptor Agonists and Interleukin-6

Abstract

The liver plays an important role in inflammation and stress by producing the acute phase proteins (APPs) required for resolution of inflammation as well as by delivering systemic glucose, through gluconeogenesis, required to fuel the stress response. Disruption of the interplay between interleukin 6 (IL-6) and glucocorticoids (GCs), the peripheral mediators of inflammation and stress, respectively, may lead to side-effects associated with the pharmacological use of GCs. The current study investigated the interplay between IL-6 and GCs in a hepatoma cell line (BWTG3) at protein (protein activity assays, Western blotting, and ELISA) and mRNA (qPCR) levels. Specifically, the action of dexamethasone (Dex), a known antiinflammatory drug and glucocorticoid receptor (GR) agonist, is compared to that of Compound A (CpdA), a selective glucocorticoid receptor agonist (SEGRA). CpdA, like IL-6, but unlike Dex, increases GR binding and decreases the metabolic enzymes, tyrosine aminotransferase, phosphoenolpyruvate carboxykinase, and gamma glutamyltransferase, at protein or mRNA level. Like Dex, both CpdA and IL-6 increase the positive APPs, serum amyloid A and C-reactive protein, and decrease the negative APP, corticosteroid binding globulin. The study shows that the GC, Dex, and IL-6 generally have divergent effects on the GR and metabolic enzymes, while their functions are convergent on the APPs. In contrast to Dex, CpdA has effects convergent to that of IL-6 on the GR, metabolic enzymes, and APPs. Thus these findings suggest that CpdA, like Dex, modulates APPs, leading to effective control of inflammation, while, in contrast to Dex, it is less likely to lead to GC-induced side-effects.

Hepatic tyrosine aminotransferase and glucocorticoid abuse in meat cattle

“…Such findings would be in contrast with the lack of a consistent rise in TAT expression observed in our study in DEX‐administered bulls, although contradictory results concerning the parallelism between TAT induction and GR levels have also emerged in human (Duret et al. , 2006) or murine cell lines (Visser et al. , 2010).…”

“…Conversely, it has been reported that veal calves or cattle treated with DEX at growth-promoting dosages exhibited little variation (Giantin et al, 2010) or even an increase in the amount of hepatic GR mRNA (Cantiello et al, 2009;Divari et al, 2011). Such findings would be in contrast with the lack of a consistent rise in TAT expression observed in our study in DEX-administered bulls, although contradictory results concerning the parallelism between TAT induction and GR levels have also emerged in human (Duret et al, 2006) or murine cell lines (Visser et al, 2010).…”

“…Our findings are difficult to compare with those from previously published studies, which were mostly performed with rat (e.g. Schuetz & Guzelian, 1984;Schmid et al, 1987) or human primary cultures (Pascussi et al, 2001) or with murine cell lines (Visser et al, 2010). Comparable results in terms of enzyme fold inductions (specific activity) were reported by Johansson et al (2005) using the same cell line.…”

“…, 1987) or human primary cultures (Pascussi et al. , 2001) or with murine cell lines (Visser et al. , 2010).…”

Impact of Glucocorticoid Receptor Density on Ligand-Independent Dimerization, Cooperative Ligand-Binding and Basal Priming of Transactivation: A Cell Culture Model

“…GR is down-regulated in response to GC exposure in most tissues [20]–[23] and in some tissues down-regulation is linked to aging [24], [25], exercise [24] and psychological stress [26], [27], while up-regulation in some tissues is linked to HIV infection [28], muscle sepsis [9], dietary restriction [29], adrenalectomy [30] and cancer [10]. In addition, GR expression levels differ greatly between tissues [5], [31] and inter-individual variances are found within the same tissue type [8], [32].…”