Endocrine Abstracts

We have previously demonstrated that a low dose of hydrocortisone (100 mg) given intravenously suppresses intranuclear NFκB and AP-1 binding and the expression of pro-inflammatory genes like MMPs. We have now investigated the effect of a high dose of hydrocortisone (300 mg=60 mg prednisolone) on NFκB binding and the expression of TLRs, the mediators of TLR signal transduction, MyD88 and TRIF and HMG-B1. Ten normal subjects were injected intravenously with 300 mg of hydrocortisone or saline in 2 separate visits one week apart in a randomized crossover study. Blood samples were obtained at 0,2,4,8 and 24 h after the injection. Mononuclear cells (MNC) were prepared by standard techniques and were tested for NFκB binding and the expression of TLRs, MyD88, TRIF, chemokines and chemokine receptors and HMG-B1. Plasma concentrations of glucose, FFAs, NO metabolites, chemokines and HMG-B1 were also measured. Following the injection of this dose, there was a significant increase in glucose concentration from 92±4 to 116±6 mg/dl, a marked increase in FFA concentrations from 0.38±0.1 to 0.804±0.15 mM. While NFκB binding and the mRNA expression of MyD88, TRIF, chemokines and chemokine receptors was suppressed significantly in MNC, the mRNA expression of TLR 2, 5 and 9 and HMG-B1 was increased (by 103±24%, 107±19%, 56±13% above the baseline, respectively) in the MNC as was the concentration of HMGB1 (by 37±12%) and MMP-9 (125±22%) in plasma. Thus, while this high dose of HC exerts a powerful anti-inflammatory effect as shown above, it also exerts certain paradoxical pro-inflammatory effects. Since both glucose and FFAs have been shown to be pro-inflammatory, it is possible that they contribute to these effects. These paradoxical pro-inflammatory effects may account for the inability of these drugs to show benefit in clinical trials of septicemia and other severe pro-inflammatory states.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.