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Activation of ß₂-Adrenoceptor Prevents Shiga Toxin 2-Induced TNF- Gene Transcription

AKIO NAKAMURA^*, EDWARD J. JOHNS, AKIRA IMAIZUMI^*, YUKISHIGE YANAGAWA^* and TAKAO KOHSAKA

^* Department of Paediatrics, Teikyo University School of Medicine, Tokyo, Japan
Department of Physiology, University of Birmingham, Birmingham, United Kingdom
Department of Immunology, National Children's Medical Centre, Tokyo, Japan.

Correspondence to Dr. Akio Nakamura, Department of Paediatrics, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173, Japan. Phone: 03-3964-1211 (ext. 1480); Fax: 03-3579-8212; E-mail: akio{at}med.teikyo-u.ac.jp

Abstract. Exposure of renal tubular epithelial cells to shiga toxin 2 (Stx-2) causes cytotoxicity, and the potency of this toxin is enhanced in the presence of tumor necrosis factor— (TNF-). It has been shown that Stx-2 induces TNF- production and that activation of ß₂-adrenoceptors downregulates TNF-. However, little is known about the signaling pathway by which ß₂-adrenoceptor agonists suppress the Stx-2—induced TNF- gene transcription. The possible signaling components involved in this pathway were investigated. Human adenocarcinoma—derived renal tubular epithelial cells (ACHN) were exposed to Stx-2 in the presence or absence of a ß₂-adrenoceptor agonist. Mitogen-activated protein kinase (MAPK), activating protein—1 (AP-1), and nuclear factor—B (NF-B) were measured to evaluate the regulatory mechanisms involved in TNF- gene transcription. Stx-2 (4 pg/ml) stimulated MAPK (p42/p44, p38) and AP-1 and increased TNF- promoter activity by 2.4-fold. The increase in TNF- was attenuated by both a p42/p44 inhibitor, PD098059 (10^-6 M), and a p38 inhibitor, SB203580 (10^-6 M), and AP-1—binding activity was inhibited by PD098059. Terbutaline (10^-6 M to 10^-8 M) suppressed MAPK (p42/p44, p38), NF-B (p50, p65), and TNF- promoter activity in a dose-dependent way that was prevented by the ß₂-adrenoceptor antagonist, ICI118,551. However, inhibition of MAPK (p42/p44) and TNF- promoter activity was partially prevented by the cAMP-protein kinase (PKA) inhibitors, H-89 (5 x 10^-6 M) and KT5720 (10^-5 M), whereas the suppression of p38 MAPK or NF-B (p50) was not blocked by these inhibitors. The suppression of NF-B (p65) was completely overcome by H-89 or KT5720. In summary, the downregulation of TNF- transcription by terbutaline was mediated by an inhibitory effect of ß₂-adrenoceptor activation on MAPK (p42/p44, p38) and NF-B (p50/p65), which were exerted through a cAMP-PKA pathway and a cAMP-independent mechanism. It is likely that cAMP-PKA and MAPK (p42/p44, p38) may play a critical role in the regulation of the Stx-2—induced TNF- transcription via ß₂-adrenoceptor activation.

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