Downregulation of glucocorticoid receptors of liver cytosols and the role of the inflammatory cytokines in pathological stress in scalded rats

Preliminary experiments indicated that target cells were resistant to glucocorticoid (GC) after pathological stress. This Study was designed to investigate the alterations in plasma corticosterone level and GC receptor (GR) of liver cytosols, to assess the relative inflammatory cytokines contribution to GC resistant, and to observe the action of alpha-melanocyte-stimulating hormone (alpha-MSH) on the potential implications of glucocorticord regulatory effects in burned rats. Male Wistar rats (weight range, 180-200 g) received a 35% total body surface area immersion scald and were randomly divided to receive either tumor necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta), polyclonal antibody (pAb), alpha-MSH, Ac-D-Lys-L-Pro-D-Val (KPV peptide), or saline (control). The binding capacity (Rt) of the steroid-binding sites was measured by radioligand binding assay, using [(3) H]dexamethasone as the ligand. We examined plasma levels of IL-1beta, TNFalpha, IL-10, and corticosterone following scald challenge in rats. The Rt of GR (208.45 +/- 30.78 fmol/mg of protein) in hepatic cytosol in rats, 12 h later the scald was significantly lower than that (306.71 +/- 27.96 fmol/mg of protein) of the control group (P < 0.01). The injections of anti-rat TNFalpha (257.80 +/- 12.82 fmol/mg of protein), IL-1beta antibody (254.46 +/- 21.21 fmol/mg of protein), alpha-melanocyte-stimulating hormone (278.32 +/- 7.76 fmol/mg of protein) and KPV peptide (263.46 +/- 17.46 fmol/mg of protein) might prevent the Rt of GR from decreasing in hepatic cytosols of rats with scald, respectively (all of P < 0.05) in vivo. Scald-induced robust increases in plasma IL-1beta (214.08 +/- 27.25 pg/ml), TNFalpha (111.18 +/- 23.97 pg/ml), U 10 (177.50 +/- 15.79 pg/ml) and corticosterone (2680 +/- 443.23 ng/ml) levels after 12 h. The administration of TNFalpha, IL-1beta pAb, alpha-MSH and KPV might attenuate these increases. These Studies suggest that pro-inflammatory cytokines are involved in downregulation of GRs and thus alpha-MSH and KPV might increase the level of GR in rats with immersion scald. (C) 2002 Elsevier Science Ltd. and ISBI. All rights reserved.