Initial and extended inflammatory messages of the nongenomic signaling pathway of the TCDD-activated Ah receptor in U937 macrophages.

Using 2,3,7,8-tetrachlorodibenzo(p)dioxin (TCDD) we have investigated the mechanisms through which the AhR elicits inflammation through the nongenomic pathway. This AhR signaling depends on the initial action of TCDD to rapidly increase the intracellular concentration of free Ca(2+), which subsequently activates cPLA2 and additional inflammatory markers (e.g. COX-2 mRNA expression) lasting up to 72h. Inhibition of cPLA2 activity resulted in attenuation of these inflammatory responses. We have hypothesized that specific protein kinases are responsible for further propagation of the initial transient nongenomic signaling into long-lasting cellular effects, and found protein kinase C (PKC) is activated at an early stage, followed by activation of cAMP-dependent protein kinase (PKA) at later stages. We clearly established in U937 macrophages cPLA2 activation is an essential initial step to activate the nongenomic inflammatory pathway of ligand-activated AhR. Furthermore, this pathway does not require the participation of ARNT, thus distinguishing itself from the classical genomic pathway.