beta(2)-adrenoceptor agonist suppresses renal tumour necrosis factor and enhances interleukin-6 gene expression induced by endotoxin.
BACKGROUND
beta(2)-Adrenoceptor activation regulates tumour necrosis factor (TNF)-alpha and interleukin-6 (IL-6) production in cultured renal cells. However, it remains uncertain whether, in vivo, the administration of beta(2)-adrenoceptor agonists regulate renal TNF-alpha and IL-6 mRNA following lipopolysaccharide (LPS) stimulation to cause endotoxaemia. This study was performed in order to evaluate the effect of beta(2)-adrenoceptor agonist on renal TNF-alpha and IL-6 production.


METHODS
Four-week-old Wistar rats pre-treated with the beta(2)-adrenoceptor agonist terbutaline or formoterol, and/or the beta- and beta(2)-adrenoceptor antagonists (propanolol, ICI118,551), were injected with LPS (1 mg i.p.), and then 2, 4 or 6 h later, kidneys (cortex, medulla), spleen, thymus and plasma were collected to assay TNF-alpha and IL-6 mRNA levels and their respective protein release.


RESULTS
Administration of beta(2)-adrenoceptor agonists suppressed TNF-alpha mRNA expression in the whole kidney, by 61% (P<0.05), as well as plasma, spleen and thymus TNF-alpha protein and mRNA expression 2 hours after injection of LPS. On the other hand, although IL-6 levels in plasma, spleen and thymus mRNA expression were suppressed significantly by administration of beta(2)-adrenoceptor agonists, the basal- and LPS-induced IL-6 mRNA levels in the whole kidney were increased 1.6- and 1.2-fold (P<0.05), respectively, by treatment with beta(2)-adrenoceptor agonists. beta(2)-Adrenoceptor agonist suppressed LPS-induced TNF-alpha mRNA expression by 35% (P<0.05) and stimulated LPS-induced IL-6 mRNA expression by 1.5-fold (P<0.05) in the medullary region of kidney.


CONCLUSIONS
beta(2)-Adrenoceptor agonists down-regulate renal TNF-alpha mRNA expression following LPS-induced endotoxaemia. This effect was particularly apparent in the renal medulla. IL-6 mRNA expression in the renal medulla was up-regulated by the agonists whereas plasma, spleen and thymus IL-6 levels were completely inhibited by the agonist, which suggests the existence of tissue specific regulation of IL-6 production in the kidney by beta(2)-adrenoceptor activation.
Nakamura
A
A
Department of Paediatrics, Teikyo University School of Medicine, Tokyo, Japan.
Johns
E J
EJ
Imaizumi
A
A
Yanagawa
Y
Y
Kohsaka
T
T
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D015536:Down-Regulation; D019446:Endotoxemia / Q000139:chemically induced / Q000378:metabolism; D004731:Endotoxins / Q000494:pharmacology*; D004983:Ethanolamines / Q000494:pharmacology; D000068759:Formoterol Fumarate; D015870:Gene Expression / Q000187:drug effects*; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics*; D007668:Kidney / Q000378:metabolism*; D008070:Lipopolysaccharides; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013726:Terbutaline / Q000494:pharmacology; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000235:genetics; D015854:Up-Regulation
D000318:Adrenergic beta-Agonists; D004731:Endotoxins; D004983:Ethanolamines; D015850:Interleukin-6; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D013726:Terbutaline; D000068759:Formoterol Fumarate