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.
Ivison
Sabine M
SM
Division of Infectious Diseases, Department of Medicine, Vancouver Coastal Research Institute (VCRI), Faculty of Medicin, University of British Columbia, Vancouver, BC, Canada V5Z 3J5.
Khan
Mohammed A S
MA
Graham
Nicholas R
NR
Shobab
Leila A
LA
Yao
Yu
Y
Kifayet
Arnawaz
A
Sly
Laura M
LM
Steiner
Theodore S
TS
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