Figure 9.

A possible mechanism for β₂-AR-induced increases in TNF-α production in PMA-treated macrophages is by increasing gene transcription of GRK 5 or 6. PMA induces an increase in protein kinase C (PKC), which activates NF-κB by phosphorylating IκBα. Phosphorylation of IκBα releases NF-κB for nuclear translocation, and subsequent DNA binding. NF-κB increases gene expression of both TNF-α and GRK5. Increased GRK5 promotes signaling of β₂-ARs in a β-arrestin-dependent manner, leading to activation of ERK1/2. ERK1/2 activates transcription factors that further promote TNF-α gene transcription to increase the production of TNF-α.