title: Delayed addition of glucocorticoids selectively suppresses cytokine production in stimulated human whole blood.
abstract: Glucocorticoids (GC) are potent drugs proven to effectively treat inflammatory diseases, although patients typically begin therapy after the onset of symptoms. Clinical studies with cytokine inhibitors prove that these mediators drive inflammatory responses in diseases such as rheumatoid arthritis and Crohn's disease. Despite the clear sequence of cytokine-induced inflammation followed by effective GC treatment, most basic science investigations have examined the ability of GC to prevent an inflammatory response rather than halt its progression. The current studies used the Toll-like receptor 2 (TLR2) agonist palmitoyl(3)-cysteine-serine-lysine(4) (PAM) or the TLR4 agonist lipopolysaccharide (LPS) to stimulate human whole blood and determine whether postponing the addition of the GC dexamethasone (DEX) limits its ability to decrease cytokine production. Twenty-four hours after stimulation, tumor necrosis factor (TNF), interleukin-1beta (IL-1beta), IL-6, and IL-8 levels were measured, in addition to the cytokine inhibitors IL-1 soluble receptor II (SRII), IL-1 receptor antagonist, and TNF SRII. LPS rapidly induced all of the proinflammatory mediators over 24 h while failing to induce any of the cytokine inhibitors. PAM stimulation also induced IL-1beta, IL-6, and IL-8. Concomitant addition of DEX plus LPS or PAM significantly suppressed all cytokine levels. Delaying the addition of DEX until 6 h after LPS stimulation failed to decrease TNF or IL-6. In contrast, delayed DEX addition significantly suppressed PAM-induced IL-1beta, IL-6, or IL-8 and also suppressed LPS-induced IL-1beta and IL-8. Our results show that cytokines which typically increase in concentration between 6 and 24 h after stimulation were significantly suppressed by the addition of DEX 6 h after stimulation.
authors.affiliation: University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Devin L
authors.initials: DL
authors.lastname: Horton
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Remick
mesh_terms: D016207:Cytokines / Q000097:blood* / Q000187:drug effects*; D003907:Dexamethasone / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D005938:Glucocorticoids / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology*; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000819:agonists* / Q000276:immunology
chemical_list: D016207:Cytokines; D005938:Glucocorticoids; D008070:Lipopolysaccharides; D051195:Toll-Like Receptor 2; D003907:Dexamethasone
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