PAR-2 activation increases human intestinal mucin secretion through EGFR transactivation

Area of Science:

• Gastroenterology
• Cell Biology
• Immunology

Background:

• Protease-activated receptor-2 (PAR-2) is a G protein-coupled receptor expressed in the intestine.
• The role of PAR-2 in regulating mucin secretion by intestinal epithelial cells remains largely uncharacterized.
• Mucin secretion is a critical component of the intestinal innate immune defense system.

Purpose of the Study:

• To investigate the effect of PAR-2 activation on mucin secretion in a human colonic goblet cell line (HT29-Cl.16E).
• To elucidate the intracellular signaling pathways mediating PAR-2-induced mucin secretion.

Main Methods:

• Constitutive expression of PAR-2 mRNA was confirmed in HT29-Cl.16E cells and primary human colonocytes.
• PAR-2 activation using the peptide SLIGKV-NH(2) and assessment of mucin secretion.
• Inhibition studies using calcium chelators (BAPTA), MAPK inhibitors (PD98059), and EGFR tyrosine kinase inhibitors (AG1478) to dissect signaling pathways.

Main Results:

• PAR-2 activation significantly stimulated mucin secretion in HT29-Cl.16E cells.
• PAR-2-induced mucin secretion was partially dependent on intracellular calcium.
• EGFR transactivation and subsequent ERK1/2 phosphorylation were identified as key mediators of PAR-2 signaling leading to mucin secretion.

Conclusions:

• Activation of PAR-2 on human intestinal epithelial cells enhances mucin secretion.
• The signaling pathway involves PAR-2-mediated EGFR transactivation, which leads to ERK1/2 activation.
• This mechanism highlights a novel role for PAR-2 in regulating intestinal innate immunity through mucin production.