NFκB and MAPK signalling pathways mediate TNFα-induced Early Growth Response gene transcription leading to aromatase expression

The Early Growth Response genes EGR2 and EGR3 play an important role in mediating TNFalpha induced aromatase expression via the adipose specific promoter PI.4. The upstream signalling pathway stimulated by TNFalpha to initiate this is unknown. The aim of this present study was to determine the signalling pathways activated by TNFalpha which result in EGR2 and EGR3 transcription, and ultimately activation of PI.4. The NFkappaB inhibitor BAY-11-7082 dose-dependently inhibited transcription of EGR2 and EGR3 mRNA as well as total and PI.4-specific CYP19A1 mRNA. The MAPK pathway inhibitor U0126, inhibitor of MEK1/2 had the same effect, however inhibition of c-Jun and JNK1,2,3 with SP600125 did not lead to down-regulation. We provide evidence for the first time that EGR2 and EGR3 are regulated by NFkappaB and MAPK signalling pathways downstream of TNFalpha stimulation in breast adipose fibroblasts, and that this in turn is upstream of CYP19A1 transcription via PI.4.