title: Prostaglandin E2 synergistically with interleukin-23 favors human Th17 expansion.
abstract: Microenvironment molecular cues direct T helper (Th) cell differentiation; however, Th17 fate determination is still imprecisely understood in humans. To assess the role of prostaglandin E(2) (PGE(2)) in Th expansion, we activated peripheral blood mononuclear cells by CD3 cross-linking. In the presence of exogenous PGE(2), peripheral blood mononuclear cells produced higher interleukin-17 (IL-17), C-C chemokine ligand 20 (CCL20)/macrophage inflammatory protein 3alpha (MIP-3alpha), CXC chemokine ligand 8 (CXCL8)/IL-8, and lower interferon-gamma and IL-22 levels than in control cultures. Exogenous PGE(2) and IL-23 synergized in inducing IL-17, whereas indomethacin and IL-23 blockade drastically reduced IL-17 but not interferon-gamma production. Furthermore, IL-1 but not tumor necrosis factor was absolutely required for IL-17 production. PGE(2) doubled the frequency of CD4+ T cells producing IL-17 and within the CD4+ subset enhanced C-C chemokine receptor 6 (CCR6) and CCR4 while decreasing CXC chemokine receptor 3 (CXCR3) expression. Furthermore, in CD4+ T-cell lines, the production of IL-17 segregated with the CCR6+ subset. In the presence of CCR6+ compared with CXCR3+ Th cells, monocytes/macrophages produced much higher levels of matrix metalloproteinase-1, -3, and -9 but similar levels of CXCL10 and IL-1beta. These results identify PGE(2) and IL-23 as participating in the expansion of CD4+ T cells endowed with high IL-17 production capacity, which in turn favors monocyte production of mediators important for host defense and tissue destruction.
authors.affiliation: Division of Immunology and Allergy, Department of Internal Medicine, University Hospital and School of Medicine, Geneva, Switzerland. chizzolini@medecine.unige.ch
authors.forename: Carlo
authors.initials: C
authors.lastname: Chizzolini
authors.forename: Rachel
authors.initials: R
authors.lastname: Chicheportiche
authors.forename: Montserrat
authors.initials: M
authors.lastname: Alvarez
authors.forename: Casimir
authors.initials: C
authors.lastname: de Rham
authors.forename: Pascale
authors.initials: P
authors.lastname: Roux-Lombard
authors.forename: Sylvie
authors.initials: S
authors.lastname: Ferrari-Lacraz
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Dayer
mesh_terms: D002460:Cell Line; D018920:Coculture Techniques; D015232:Dinoprostone / Q000008:administration & dosage* / Q000378:metabolism; D004357:Drug Synergism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020381:Interleukin-17 / Q000096:biosynthesis*; D053759:Interleukin-23 / Q000008:administration & dosage* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000096:biosynthesis; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D054398:Receptors, CCR4 / Q000378:metabolism; D054399:Receptors, CCR6 / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism
chemical_list: C515354:CCR4 protein, human; C106311:CCR6 protein, human; D007375:Interleukin-1; D020381:Interleukin-17; D053759:Interleukin-23; D054398:Receptors, CCR4; D054399:Receptors, CCR6; D011994:Recombinant Proteins; D007371:Interferon-gamma; D020782:Matrix Metalloproteinases; D015232:Dinoprostone