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PAR2 triggers IL-8 release via MEK/ERK and PI3-kinase/Akt pathways in GI epithelial cells

Yusuke Tanaka1, Fumiko Sekiguchi1, Hao Hong1

  • 1Division of Pharmacology and Pathophysiology, Kinki University School of Pharmacy, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan.

Biochemical and Biophysical Research Communications
|October 16, 2008
PubMed

Insights

Proteinase-activated receptor-2 (PAR2) triggers interleukin-8 (IL-8) release in gastrointestinal cells. This inflammatory response is mediated by two independent signaling pathways: MEK/ERK and PI3-kinase/Akt.

Area of Science:

  • Gastroenterology
  • Cellular Signaling
  • Immunology

Background:

  • Proteinase-activated receptor-2 (PAR2) is implicated in pro-inflammatory responses within the gastrointestinal (GI) tract.
  • Understanding the specific downstream signaling pathways activated by PAR2 in GI epithelial cells is crucial for elucidating its role in inflammation.

Purpose of the Study:

  • To investigate the downstream signaling mechanisms by which PAR2 stimulation leads to interleukin-8 (IL-8) release in human GI epithelial cells.

Main Methods:

  • Utilized human colorectal cancer (HCT-15) and gastric adenocarcinoma (MKN-45) cell lines.
  • Stimulated cells with a PAR2-activating peptide and assessed IL-8 release.
  • Employed MEK inhibitor (U0126) and PI3-kinase inhibitor (LY294002) to block specific signaling pathways.
  • Monitored the phosphorylation status of ERK and Akt kinases.

Main Results:

  • PAR2 activation, but not PAR1 activation or scrambled peptide, induced IL-8 release from GI epithelial cells.
  • PAR2 stimulation led to the activation of both ERK and Akt kinases.
  • Inhibitors U0126 and LY294002 selectively blocked ERK and Akt phosphorylation, respectively.
  • Inhibition of MEK/ERK or PI3-kinase/Akt pathways attenuated PAR2-induced IL-8 release.

Conclusions:

  • PAR2 activation in GI epithelial cells triggers IL-8 release through two distinct and independent intracellular signaling cascades: the MEK/ERK pathway and the PI3-kinase/Akt pathway.
  • These findings reinforce the role of PAR2 as a pro-inflammatory receptor in the gastrointestinal system.

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