Suppression of tumor necrosis factor-alpha by beta2-adrenoceptor activation: role of mitogen-activated protein kinases in renal mesangial cells.
OBJECTIVE
The present study examined the inhibitory effect of beta2-adrenoceptor activation on the mitogen-activated protein kinase (MAPK) cascades and the contribution of these pathways to the suppression of tumor necrosis factor (TNF)-alpha in lipopolysaccharide (LPS)-stimulated rat renal mesangial cells.


METHODS
Experiments were performed using cultured mesangial cells in the presence of LPS (1 microg/ml) and/or the beta2-adrenoceptor agonist, terbutaline (10(-6) 10(-8) M). The levels of extracellular signal-regulated kinase-1 and 2(Erk 1/2), p38, c-Jun N-terminal protein kinase (JNK) and TNF-alpha 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(-8) M) in a dose dependent way. These inhibitory actions of terbutaline were prevented by the beta2-adrenoceptor antagonist, ICI 118,551(10(-6) M) but not by an inhibitor of the cAMP-PKA pathway, H-89 (5 x 10(-6) M). The selective MAPK/Erk-1 inhibitor, PD98059 (10(-5) M) and the specific p38 inhibitor SB203580 (10(-5) M) significantly decreased LPS-induced TNF-alpha production in the cells.


CONCLUSIONS
Inhibition of MAPK cascades (Erkl/2 and p38) plays an important role in the suppression of TNF-alpha following beta2-adrenoceptor activation but the inhibitory effect on MAPK is independent of the cAMP-PKA pathway in the mesangial cell.
Nakamura
A
A
Department of Paediatrics, Teikyo University School of Medicine, Tokyo, Japan 173. akio@med.teikyo-u.ac.jp
Imaizumi
A
A
Yanagawa
Y
Y
Niimi
R
R
Kohsaka
T
T
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides; D013726:Terbutaline / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D048051:p38 Mitogen-Activated Protein Kinases
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D007546:Isoquinolines; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D013726:Terbutaline