Suppression of tumor necrosis factor-α by β₂-adrenoceptor activation: role of mitogen-activated protein kinases in renal mesangial cells

Abstract:

Objective: The present study examined the inhibitory effect of β₂-adrenoceptor activation on the mitogen-activated protein kinase (MAPK) cascades and the contribution of these pathways to the suppression of tumor necrosis factor (TNF)-α in lipopolysaccharide (LPS)-stimulated rat renal mesangial cells.¶Materials and Methods: Experiments were performed using cultured mesangial cells in the presence of LPS (1 μg/ml) and/or the β₂-adrenoceptor agonist, terbutaline (10^–6– 10^–8M). The levels of extracellular signal-regulated kinase-1 and 2(Erk1/2), p38, c-Jun N-terminal protein kinase (JNK) and TNF-α were estimated.¶Results: LPS activated Erk-1/2 and p38 levels, by 4.7-fold and 1.8-fold, respectively (P <0.05), which were suppressed by terbutaline (10^–6–10^–8M) in a dose dependent way. These inhibitory actions of terbutaline were prevented by the β₂-adrenoceptor antagonist, ICI 118,551(10^–6M) but not by an inhibitor of the cAMP-PKA pathway, H-89 (5 × 10^–6 M). The selective MAPK/Erk-1 inhibitor, PD98059 (10^–5M) and the specific p38 inhibitor SB203580 (10^–5M) significantly decreased LPS-induced TNF-α production in the cells.¶Conclusions: Inhibition of MAPK cascades (Erk1/2 and p38) plays an important role in the suppression of TNF-α following β₂-adrenoceptor activation but the inhibitory effect on MAPK is independent of the cAMP-PKA pathway in the mesangial cell.