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Activation of beta(2)-adrenoceptor prevents shiga toxin 2-induced TNF-alpha gene transcription

Akio Nakamura1, Edward J Johns2, Akira Imaizumi1

  • 1Department of Paediatrics, Teikyo University School of Medicine, Tokyo, Japan.

Journal of the American Society of Nephrology : JASN
|October 25, 2001
PubMed

Insights

Beta(2)-adrenoceptor agonists suppress Shiga toxin 2-induced TNF-alpha gene transcription by inhibiting MAPK and NF-kappa B signaling pathways. This mechanism involves both cAMP-dependent and independent pathways, highlighting a novel therapeutic target.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Pharmacology

Background:

  • Shiga toxin 2 (Stx-2) exposure induces renal tubular epithelial cell cytotoxicity.
  • Tumor necrosis factor-alpha (TNF-alpha) enhances Stx-2 potency and is induced by Stx-2.
  • Beta(2)-adrenoceptor activation downregulates TNF-alpha, but the underlying signaling pathway remains unclear.

Purpose of the Study:

  • To investigate the signaling pathway through which beta(2)-adrenoceptor agonists suppress Stx-2-induced TNF-alpha gene transcription.
  • To elucidate the roles of Mitogen-activated protein kinase (MAPK), activating protein-1 (AP-1), and nuclear factor-kappa B (NF-kappa B) in this process.

Main Methods:

  • Human renal tubular epithelial cells (ACHN) were treated with Stx-2 and a beta(2)-adrenoceptor agonist (terbutaline).
  • Key signaling molecules including MAPK (p42/p44, p38), AP-1, NF-kappa B (p50, p65), and TNF-alpha promoter activity were measured.
  • Specific inhibitors for MAPK (PD098059, SB203580), beta(2)-adrenoceptor (ICI118,551), and cAMP-protein kinase (PKA) (H-89, KT5720) were utilized.

Main Results:

  • Stx-2 stimulated MAPK (p42/p44, p38), AP-1, and TNF-alpha promoter activity.
  • Terbutaline dose-dependently suppressed MAPK, NF-kappa B, and TNF-alpha promoter activity, an effect blocked by ICI118,551.
  • cAMP-PKA pathway inhibitors partially blocked MAPK (p42/p44) and TNF-alpha suppression, while fully blocking NF-kappa B (p65) suppression, indicating both cAMP-dependent and independent mechanisms.

Conclusions:

  • Beta(2)-adrenoceptor activation downregulates Stx-2-induced TNF-alpha transcription via inhibition of MAPK (p42/p44, p38) and NF-kappa B (p50/p65).
  • This regulation involves both cAMP-PKA-dependent and independent signaling pathways.
  • These findings suggest a critical role for cAMP-PKA and MAPK in mediating the effects of beta(2)-adrenoceptor activation on Stx-2-induced TNF-alpha transcription.

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