Abstract
BackgroundGlucocorticoids (GCs) have been extensively used as essential modulators in clinical infectious and inflammatory diseases. The GC receptor (GR) is a transcription factor belonging to the nuclear receptor family that regulates anti-inflammatory processes and releases pro-inflammatory cytokines, such as interleukin (IL)-6.ResultsFive putative GR binding sites and other transcriptional factor binding sites were identified on theIL-6 promoter, and dexamethasone (DEX) was noted to reduce the lipopolysaccharide (LPS)-induced IL-6 production. Among mutant transcriptional factor binding sites, nuclear factor-kappa B (NF-κB), activator protein (AP)-1, and specificity protein (Sp)1–2 sites reduced basal and LPS-induced IL-6 promoter activities through various responses. The second GR binding site (GR2) was noted to play a crucial role in both basal and inducible promoter activities in LPS-induced inflammation.ConclusionsWe concluded that selective GR2 modulator might exert agonistic and antagonistic effects and could activate crucial signaling pathways during the LPS-stimulated inflammatory process.
Highlights
Glucocorticoids (GCs) have been extensively used as essential modulators in clinical infectious and inflammatory diseases
We previously demonstrated an increase in the macrophage migration inhibitory factor (MIF) in severe sepsis conditions, such as in the Vibrio vulnificus-infected model [19]
We observed that the morphology of RAW 264.7 cells was changed under LPS treatment to perform macrophage-like activities and accompanied the cytokine gene expression, such as IL-6 (Fig. 1a)
Summary
Glucocorticoids (GCs) have been extensively used as essential modulators in clinical infectious and inflammatory diseases. The GC receptor (GR) is a transcription factor belonging to the nuclear receptor family that regulates anti-inflammatory processes and releases pro-inflammatory cytokines, such as interleukin (IL)-6. Severe sepsis is related to immune dysequilibrium. Immune dysregulation during the early phase of sepsis results from the inadequate endogenous glucocorticoid (GC)-mediated regulation of nuclear factor-κВ (NF-κВ) activation, which leads to its overexpression and release of massive proinflammatory cytokines (the so-called “cytokine storm”) [1]. “GC sensitivity” in critically ill patients with septic shock is associated with disease severity and outcome [2]. Low-dose steroid administration during the early septic phase. GCs modulate the innate and adaptive immune systems responding to infection in mammals. Toll-like receptors (TLRs) are wellknown pattern-recognition receptors and are responsible
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