Intestinal expression of Fas and Fas ligand is upregulated by bacterial signaling through TLR4 and TLR5, with activation of Fas modulating intestinal TLR-mediated inflammation.
TLRs play an important role in mediating intestinal inflammation and homeostasis. Fas is best studied in terms of its function in apoptosis, but recent studies demonstrate that Fas signaling may mediate additional functions such as inflammation. The role of Fas, and the Fas ligand (FasL), in the intestine is poorly understood. The aim of this study was to evaluate potential cross-talk between TLRs and Fas/FasL system in intestinal epithelial cells (IECs). IECs were stimulated with TLR ligands, and expression of Fas and FasL was investigated. Treatment with TLR4 and TLR5 ligands, but not TLR2 and 9 ligands, increased expression of Fas and FasL in IECs in vitro. Consistent with this finding, expression of intestinal Fas and FasL was reduced in vivo in the epithelium of TLR4 knockout (KO), 5KO, and germ-free mice, but not in TLR2KO mice. Modulating Fas signaling using agonistic anti-Fas augmented TLR4- and TLR5-mediated TNF-α and IL-8 production by IECs. In addition, suppression of Fas in IECs reduced the ability of TLR4 and TLR5 ligands and the intestinal pathogens Salmonella typhimurium and Listeria monocytogenes to induce the expression of IL-8. In conclusion, this study demonstrates that extensive cross-talk in IECs occurs between the Fas and TLR signaling pathways, with the FasL/Fas system playing a role in TLR-mediated inflammatory responses in the intestine.
Department of Medicine, University College Cork, Cork, Ireland;
Philana
P
Fernandes
Department of Medicine, University College Cork, Cork, Ireland;
Charlotte
C
O'Donnell
Department of Pathology, University College Cork, Cork, Ireland;
Caitriona
C
Lyons
Department of Pathology, University College Cork, Cork, Ireland;
Jonathan
J
Keane
Department of Pathology, University College Cork, Cork, Ireland;
Tim
T
Regan
Department of Pathology, University College Cork, Cork, Ireland;
Stephen
S
O'Brien
Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; and.
Padraic
P
Fallon
Department of Pathology, University College Cork, Cork, Ireland; Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland e.brint@ucc.ie.
Elizabeth
E
Brint
Department of Medicine, University College Cork, Cork, Ireland; Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
Aileen
A
Houston
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D019073:HT29 Cells; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism*; D007422:Intestines / Q000276:immunology / Q000382:microbiology; D008024:Ligands; D008089:Listeria monocytogenes; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D012486:Salmonella typhimurium; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D051198:Toll-Like Receptor 5 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D019014:fas Receptor / Q000819:agonists / Q000235:genetics / Q000378:metabolism*
D016207:Cytokines; D053222:Fas Ligand Protein; D008024:Ligands; D016328:NF-kappa B; D051197:Toll-Like Receptor 4; D051198:Toll-Like Receptor 5; D019014:fas Receptor; D019869:Phosphatidylinositol 3-Kinases