More than a decade ago our view of gene regulation by glucocorticoids (GC) and other steroid hormones underwent a dramatic change with the discovery of negative crosstalk (transcriptional interference) between the GC receptor (GCR) and transcription factor AP-1 (Jun:Fos). It was initially observed that induction of the collagenase type 1 gene, which is mediated through activation of AP-1 by growth factors and inflammatory cytokines, is repressed by GC. This repression was attributed to mutual negative interactions between AP-1 and GCR. Although the exact molecular mechanism underlying this particular case of transcriptional interference is yet to be determined, it has become clear that this and analogous interactions with other transcription factors (e.g. nuclear factor-kappaB) underlie the anti-inflammatory and immunosuppressive activity of GC. Recent studies conducted at the whole animal level indicate that the interactions between the AP-1 and GC signaling pathways are much more extensive. AP-1-related signaling via the Jun N-terminal kinases can lead to increased levels of circulating GC, which eventually down-modulate AP-1 activity via transcriptional interference. This negative feedback loop is likely to be of great importance for maintenance of homeostasis and regulation of stress responses, including acute and chronic inflammation.

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