How are the antiinflammatory effects of Glucocorticoids mediated

How are the antiinflammatory effects of Glucocorticoids mediated?

GCs have beneficial antiinflammatory effects through numerous mechanisms. Some of the most important are:

  • • Genomic.
    • Higher dose GCs diffuse passively across cell membranes, bind to and activate cytoplasmic GC receptors (cGCRs) causing release from their chaperone proteins (heat shock protein-90, etc). The GC–cGRC complex homodimerizes, enters the nucleus, and binds to GC response elements on DNA. This complex on the DNA binds CREB-binding proteins, which acetylate histones exposing genes that code for antiinflammatory proteins (IL-10, IκB, etc).
    • Low-dose GCs diffuse across cell membranes, bind to and activate intracellular cGCRs, enter the nucleus, and interact with proinflammatory transcription factors (NF-κB, AP-1, etc) that have bound to DNA. This complex then recruits HDAC2, which deacetylates histones resulting in the inhibition of genes causing decreased production of proinflammatory molecules (cytokines, chemokines, adhesion molecules, COX-2, etc).
    • GCs saturate the cGCRs at doses of ≤30 mg/day of prednisone. Higher doses have few genomic effects. GCs take >30 minutes to exert their genomic effects.
  • • Nongenomic.
    • GCs bind to cGCRs causing release of inhibitory proteins such as Src. This effect occurs with low-dose GCs within seconds to minutes.
    • GCs at doses ≥30 mg/day of prednisone bind to membrane GC receptors on lymphocytes and monocytes leading to antiinflammatory effects.
    • GCs at very high doses (>100 mg/day of prednisone) intercalate into cell membranes reducing calcium and sodium cycling across the membrane, which has antiinflammatory effects. This may explain differential effects of high-dose “pulse” steroids.

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