PAR2 triggers IL-8 release via MEK/ERK and PI3-kinase/Akt pathways in GI epithelial cells.
Proteinase-activated receptor-2 (PAR2) plays pro-inflammatory roles in many organs including the gastrointestinal (GI) tract. To clarify the downstream pro-inflammatory signaling of PAR2 in the GI tract, we examined interleukin-8 (IL-8) release and the underlying cellular signaling following PAR2 stimulation in human colorectal cancer-derived HCT-15 cells and human gastric adenocarcinoma-derived MKN-45 cells. A PAR2-activating peptide, but not a PAR2-inactive scrambled peptide or a PAR1- activating peptide, caused IL-8 release in these GI epithelial cells. The PAR2-triggered IL-8 release was suppressed by inhibitors of MEK (U0126) or PI3-kinase (LY294002), and PAR2 stimulation indeed activated the downstream kinases, ERK and Akt. U0126 blocked the phosphorylation of ERK, but not Akt, and LY294002 blocked the phosphorylation of Akt, but not ERK. Together, PAR2 triggers IL-8 release via two independent signaling pathways, MEK/ERK and PI3-kinase/Akt, suggesting a role of PAR2 as a pro-inflammatory receptor in the GI tract.
Division of Pharmacology and Pathophysiology, Kinki University School of Pharmacy, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan.
Yusuke
Y
Tanaka
Division of Pharmacology and Pathophysiology, Kinki University School of Pharmacy, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan.
Fumiko
F
Sekiguchi
Division of Pharmacology and Pathophysiology, Kinki University School of Pharmacy, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan.
Hao
H
Hong
Division of Pharmacology and Pathophysiology, Kinki University School of Pharmacy, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan. Electronic address: kawabata@phar.kindai.ac.jp.
Atsufumi
A
Kawabata
D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000502:physiology*
D002070:Butadienes; D002867:Chromones; D048049:Extracellular Signal-Regulated MAP Kinases; D016209:Interleukin-8; D020930:MAP Kinase Kinase Kinases; D009025:Morpholines; D009570:Nitriles; D010455:Peptides; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D044464:Receptor, PAR-2; C113580:U 0126; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one