title: Human intestinal epithelial cells express interleukin-10 through Toll-like receptor 4-mediated epithelial-macrophage crosstalk.
abstract: In the intestine, interaction between epithelial cells and macrophages (MΦs) create a unique immunoregulatory microenvironment necessary to maintain local immune and tissue homeostasis. Human intestinal epithelial cells (IECs) have been shown to express interleukin (IL)-10, which keeps epithelial integrity. We have demonstrated that bacterial signaling through Toll-like receptor (TLR) 4 induces 15-deoxy-Δ-12,14-prostaglandin J2 (15d-PGJ2) synthesis in intestinal MΦs by cyclooxygenase (Cox)-2 expression. Here, we show that TLR4 signaling generates crosstalk between IECs and MΦs that enhances IL-10 expression in IECs. Direct stimulation of TLR4 leads to the expression of IL-10 in IECs, while the presence of MΦs in a Transwell system induces another peak in IL-10 expression in IECs at a later time point. The second peak of the IL-10 expression is two times greater than the first peak. This late induction of IL-10 depends on the nuclear receptor peroxisome proliferator-activated receptor (PPAR) γ that is accumulated in IECs by TLR4-mediated inhibition of the ubiquitin-proteasomal pathway. TLR4 signaling in MΦs in turn synthesizes 15d-PGJ2 through p38 and ERK activation and Cox-2 induction, which activates PPARγ in IECs. These results suggest that TLR4 signaling maintains IL-10 production in IECs by generating epithelial-MΦs crosstalk, which is an important mechanism in the maintenance of intestinal homeostasis mediated through host-bacterial interactions.
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of Miami Miller School of Medicine, Miami, Fla., USA.
authors.forename: Jinhee
authors.initials: J
authors.lastname: Hyun
authors.forename: Laura
authors.initials: L
authors.lastname: Romero
authors.forename: Reldy
authors.initials: R
authors.lastname: Riveron
authors.forename: Claudia
authors.initials: C
authors.lastname: Flores
authors.forename: Saravana
authors.initials: S
authors.lastname: Kanagavelu
authors.forename: Kristina D
authors.initials: KD
authors.lastname: Chung
authors.forename: Ana
authors.initials: A
authors.lastname: Alonso
authors.forename: John
authors.initials: J
authors.lastname: Sotolongo
authors.forename: Jose
authors.initials: J
authors.lastname: Ruiz
authors.forename: Armine
authors.initials: A
authors.lastname: Manukyan
authors.forename: Sally
authors.initials: S
authors.lastname: Chun
authors.forename: Gaurav
authors.initials: G
authors.lastname: Singh
authors.forename: Pedro
authors.initials: P
authors.lastname: Salas
authors.forename: Stephan R
authors.initials: SR
authors.lastname: Targan
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fukata
mesh_terms: D002450:Cell Communication / Q000276:immunology*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000276:immunology; D004847:Epithelial Cells / Q000276:immunology*; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology*; D007413:Intestinal Mucosa / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology*
chemical_list: C477819:15-deoxyprostaglandin J2; C508609:IL10 protein, human; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D016753:Interleukin-10; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D015230:Prostaglandin D2