title: A mixed anti-inflammatory and pro-inflammatory response associated with a high dose of corticosteroids.
abstract: OBJECTIVE
  Hydrocortisone, at a low dose (100 mg), induces an anti-inflammatory response including inducing IkBα and suppressing intranuclear NFκB and AP-1 binding and the expression of pro-inflammatory mediators like MMPs. We have now investigated the effect of a high dose of hydrocortisone (300mg=60 mg prednisolone) on NFκB binding and the expression of TLRs, the mediators of TLR signal transduction, MyD88 and TRIF and HMG-B1.
  
  
  METHODS
  A 300mg of hydrocortisone or saline was injected intravenously in ten normal subjects during 2 separate visits, in a randomized crossover study. Blood samples were obtained at 0, 1, 4, 6 and 24h after the injection and mononuclear cells (MNC) were prepared.
  
  
  RESULTS
  There was a significant increase in glucose (from 92±4 to 116±6 mg/dl), insulin (from 4.5±0.7 to 5.3±0.8 mU/ml) and FFA concentrations (from 0.38±0.1 to 0.80±0.15mM) following the administration of hydrocortisone compared to placebo treatment. While NFκB binding and the mRNA expression of MyD88, TRIF, chemokines and chemokine receptors were suppressed significantly in MNC, there was a paradoxical increase in the mRNA expression of TLR 2, 5 and 9 and HMG-B1 was increased by 103±24%, 107±19%, 56±13% and 58±12% above the baseline, respectively in the MNC. Plasma concentrations of HMG-B1 and MMP-9 increased by 37±12% and 125±22%, respectively, while TNF-α concentrations fell by 27±9%.
  
  
  CONCLUSIONS
  While this high dose of hydrocortisone exerts a powerful anti-inflammatory effect, it also exerts certain proinflammatory effects mainly on TLRs expression. The known pro-inflammatory effects of glucose and FFAs may have contributed 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 and might contribute to some of the side effects of corticosteroids use.
authors: P
authors: P
authors: Dandona
authors: H
authors: H
authors: Ghanim
authors: C L
authors: CL
authors: Sia
authors: K
authors: K
authors: Green
authors: S
authors: S
authors: Abuaysheh
authors: S
authors: S
authors: Dhindsa
authors: A
authors: A
authors: Chaudhuri
authors: Division of Endocrinology, State University of New York at Buffalo, 115 Flint Rd, Williamsville, NY 14221, USA. pdandona@KaleidaHealth.org.
authors: A
authors: A
authors: Makdissi
mesh_terms: D000305:Adrenal Cortex Hormones / Q000008:administration & dosage*; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D001786:Blood Glucose; D018925:Chemokines / Q000378:metabolism; D018592:Cross-Over Studies; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D024243:HMGB1 Protein / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000008:administration & dosage*; D007328:Insulin / Q000097:blood; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D055815:Young Adult
chemical_list: D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D001786:Blood Glucose; D018925:Chemokines; D005230:Fatty Acids, Nonesterified; D024243:HMGB1 Protein; D018836:Inflammation Mediators; D007328:Insulin; D016328:NF-kappa B; D019707:Receptors, Chemokine; D014409:Tumor Necrosis Factor-alpha; D020780:Matrix Metalloproteinase 9