TUMOR NECROSIS FACTOR-α INHIBITS ANGIOTENSIN II RECEPTOR TYPE 1 EXPRESSION IN DORSAL ROOT GANGLION NEURONS VIA β-CATENIN SIGNALING

Both tumor necrosis factor (TNF)-alpha and the angiotensin (Ang) II/angiotensin II receptor type 1 (AT1) axis play important roles in neuropathic pain and nociception. In the present study, we explored the interaction between the two systems by examining the mutual effects between TNF-alpha and the Ang II/AT1 receptor axis in dorsal root ganglion (DRG) neurons. Rat DRG neurons were treated with TNF-alpha in different concentrations for different lengths of time in the presence or absence of transcription inhibitor actinomycin D, TNF receptor 1 (TNFR1) inhibitor SPD304, p-catenin signaling inhibitor CCT031374, or different kinase inhibitors. TNF-alpha decreased the AT1 receptor mRNA level as well as the AT1a receptor promoter activity in a dose-dependent manner within 30 h, which led to dose-dependent inhibition of Ang II-binding AT1 receptor level on the cell membrane. Actinomycin D (1 mg/ml), SPD304 (50 mu M), p38 mitogen-activated protein kinase (MAPK) inhibitor PD169316 (25 mu M), and CCT031374 (50 mu M) completely abolished the inhibitory effect of TNF-alpha on AT1 receptor expression. TNF-alpha dose-dependently increased soluble beta-catenin and phosphorylated GSK-3 beta levels, which was blocked by SPD304 and PD169316. In DRG neurons treated with AT2 receptor agonist CGP421140, or Ang II with or without AT1 receptor antagonist losartan or AT2 receptor antagonist PD123319 for 30 h, we found that Ang II and Ang II + PD123319 significantly decreased TNF-alpha expression, whereas CPG421140 and Ang II + losartan increased TNF-alpha expression. In conclusion, we demonstrate that TNF-alpha inhibits AT1 receptor expression at the transcription level via TNFR1 in rat DRG neurons by increasing the soluble beta-catenin level through the p38 MAPK/GSK-3 beta pathway. In addition, Ang II appears to inhibit and induce TNF-alpha expression via the AT1 receptor and the AT2 receptor in DRG neurons, respectively. This is the first evidence of crosstalk