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.