Activation of (cid:1) 2 -Adrenoceptor Prevents Shiga Toxin 2-Induced TNF- (cid:2) Gene Transcription

. 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– (cid:2) (TNF- (cid:2) ). It has been shown that Stx-2 induces TNF- (cid:2) production and that activation of (cid:1) 2 -adrenoceptors downregulates TNF- (cid:2) . However, little is known about the signaling pathway by which (cid:1) 2 -adrenoceptor agonists suppress the Stx-2–induced TNF- (cid:2) gene transcription. The possible signaling components involved in this pathway were investigated. Human adenocar-cinoma–derived renal tubular epithelial cells (ACHN) were exposed to Stx-2 in the presence or absence of a (cid:1) 2 -adreno-ceptor agonist. Mitogen-activated protein kinase (MAPK), activating protein–1 (AP-1), and nuclear factor– (cid:3) B (NF- (cid:3) B) were measured to evaluate the regulatory mechanisms involved in TNF- (cid:2) gene transcription. Stx-2 (4 pg/ml) stimulated MAPK (p42/p44, p38) and AP-1 and increased TNF- (cid:2) promoter activity by 2.4-fold. The increase in TNF- (cid:2) was attenuated by both a p42/p44 inhibitor, PD098059 (10

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