Table 2.

Molecular mechanisms of glucocorticoid resistance

•Familial glucocorticoid resistance

•Glucocorticoid receptor modification

Phosphorylation: decreased nuclear translocation

p38 MAP kinase due to IL-2 + IL-4 or IL-13 in severe asthma

p38 MAP kinase due to MIF in several inflammatory diseases

JNK due to pro-inflammatory cytokines

ERK due to microbial superantigens

Nitrosylation: ↑ NO from inducible NO synthase

Ubiquitination: ↑ degradation by proteasome

•Increased GRβ expression

•Increased pro-inflammatory transcription factors

Activator protein-1, JNK

STAT5, JAK3

•Defective histone acetylation

Decreased acetylation of lysine-5 on histone 4

Decreased histone deacetylase-2

↑ oxidative stress

↑ phosphoinositide-3-kinase-δ activation

•Increased P-glycoprotein

Increased efflux of steroids

ERK, extracellular signal-regulated kinase; IL, interleukin; JNK, c-Jun N-terminal kinase; MAP, mitogen-activated protein; MIF, macrophage migration inhibitory factor; NO, nitric oxide; STAT, signal transduction activated transcription factor.