Figure 3.

Glucocorticoid receptor (GR)-mediated repression of the proinflammatory transcription factors AP-1 and NF-κB. (a) Proinflammatory stimuli trigger a signaling cascade that results in the activation of the transcription factor, AP-1, a heterodimer composed of c-Jun and c-Fos. This drives the transcription of several proinflammatory molecules. Activation of the GR results in its translocation to the nucleus where it can now repress AP-1 activity via one of three mechanisms: (i) at some promoters, GR physically interacts with c-Jun in a process known as tethering, which represses the activity of AP-1 and represses the transcription of proinflammatory genes; (ii) at some promoters, GR is able to simultaneously bind to a GRE and tether to c-Jun to repress the transcriptional activity of AP-1; and (iii) GR induces the expression of MKP-1, a phosphatase, that is able to dephosphorylate and inactivate the kinase JNK. (b) Proinflammatory stimuli trigger a signaling cascade that results in the activation of the transcription factor, NF-κB, a heterodimer composed of the p50 and p65 subunits. This drives the transcription of several proinflammatory genes. Although the exact mechanism is not known, there are several theories as to how GR can inhibit NF-κB activity: (i) similarly to AP-1, GR can physically interact with and repress the activity of NF-κB; (ii) GR is able to block the formation of an NF-κB/IRF3 heterodimer, possibly through the recruitment of GRIP; (iii) GR is able to block the recruitment of the C-terminal tail kinase, pTEFb, thus preventing RNA polymerase II (Pol II) phosphorylation and activation; (iv) GR is able to repress NF-κB activity by recruiting a histone deacetylase (HDAC); (v) GR is able to block the ability of NF-κB to interact with p300 and CPB; and (vi) p53 is able to interact with GR, altering its transcriptional activity, and thus preventing NF-κB activity.