The p110α and p110β isoforms of class I phosphatidylinositol 3-kinase are involved in toll-like receptor 5 signaling in epithelial cells.
BACKGROUND
Bacterial flagellin triggers inflammation in mammalian cells via Toll-like receptor (TLR) 5. Release of the chemokine IL-8 in response to flagellin involves NF-κB, p38 MAP kinase, and phosphatidylinositol 3-kinase (PI3K). However, PI3K has been reported to be either pro- or anti-inflammatory in different model systems. We hypothesized that this could be due to different activities of the p110α and β isoforms of PI3K.


RESULTS
PI3K and Akt were rapidly activated in Caco-2 colon carcinoma cells by flagellin. Using a plasmid-based shRNA delivery system and novel p110 isoform-specific inhibitors, we found that flagellin-induced IL-8 production was dependent on both p110α and p110β. However in the mouse, inhibition of p110β but not p110α reduced the increase of serum IL-6 levels induced by intraperitoneal injection of flagellin.


CONCLUSIONS
These data demonstrate that the p110α and β isoforms of class IA PI3K are both required for the proinflammatory response to flagellin.
Division of Infectious Diseases, Department of Medicine, Vancouver Coastal Research Institute (VCRI), Faculty of Medicin, University of British Columbia, Vancouver, BC, Canada V5Z 3J5.
Sabine M
SM
Ivison
Mohammed A S
MA
Khan
Nicholas R
NR
Graham
Leila A
LA
Shobab
Yu
Y
Yao
Arnawaz
A
Kifayet
Laura M
LM
Sly
Theodore S
TS
Steiner
D000818:Animals; D018938:Caco-2 Cells; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology*; D006801:Humans; D007249:Inflammation; D015850:Interleukin-6 / Q000097:blood; D016209:Interleukin-8 / Q000097:blood / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms; D051198:Toll-Like Receptor 5 / Q000378:metabolism*
D015850:Interleukin-6; D016209:Interleukin-8; D020033:Protein Isoforms; C495346:TLR5 protein, human; D051198:Toll-Like Receptor 5; D019869:Phosphatidylinositol 3-Kinases; D058543:Class Ia Phosphatidylinositol 3-Kinase