Activation of ROS/NF-kappaB and Ca2+/CaM kinase II are necessary for VCAM-1 induction in IL-1beta-treated human tracheal smooth muscle cells

Toxicol Appl Pharmacol. 2009 May 15;237(1):8-21. doi: 10.1016/j.taap.2009.02.025. Epub 2009 Mar 10.

Abstract

Histone acetylation regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs) plays a critical role in the expression of inflammatory genes, such as vascular cell adhesion molecule-1 (VCAM-1). Oxidative processes have been shown to induce VCAM-1 expression. Here, we investigated the mechanisms underlying IL-1beta-induced VCAM-1 expression in human tracheal smooth muscle cells (HTSMCs). Our results showed that IL-1beta enhanced HTSMCs-monocyte adhesion through up-regulation of VCAM-1, which was inhibited by pretreatment with selective inhibitors of PKCalpha (Gö6976), c-Src (PP1), NADPH oxidase [diphenylene iodonium (DPI) and apocynin (APO)], intracellular calcium chelator (BAPTA/AM), PI-PLC (U73122), CaM (calmidazolium chloride), CaM kinase II (KN62), p300 (garcinol), NF-kappaB (Bay11-7082), HDAC (trichostatin A), and ROS scavenger [N-acetyl-L-cysteine (NAC)] or transfection with siRNAs of MyD88, PKCalpha, Src, p47(phox), p300, and HDAC4. Moreover, IL-1beta stimulated NF-kappaB and CaMKII phosphorylation through MyD88-dependent PI-PLC/PKCalpha/c-Src/ROS and PI-PLC/Ca2+/CaM pathways, respectively. Activation of NF-kappaB and CaMKII may eventually lead to the acetylation of histone residues and phosphorylation of histone deacetylases. These findings suggested that IL-1beta induced VCAM-1 expression via these multiple signaling pathways in HTSMCs. Blockade of these pathways may reduce monocyte adhesion via VCAM-1 suppression and attenuation of the inflammatory responses in airway diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Adaptation, Physiological
  • Airway Resistance / physiology
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
  • Cells, Cultured
  • Histones / metabolism
  • Humans
  • Interleukin-1beta / administration & dosage
  • Interleukin-1beta / immunology
  • Interleukin-1beta / physiology*
  • Myocytes, Smooth Muscle / immunology
  • Myocytes, Smooth Muscle / metabolism*
  • NF-kappa B / metabolism*
  • Reactive Oxygen Species / metabolism
  • Second Messenger Systems / physiology
  • Signal Transduction / physiology
  • Trachea / cytology
  • Trachea / metabolism
  • Up-Regulation
  • Vascular Cell Adhesion Molecule-1 / metabolism*

Substances

  • Histones
  • Interleukin-1beta
  • NF-kappa B
  • Reactive Oxygen Species
  • Vascular Cell Adhesion Molecule-1
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2