title: Negative regulation of IL-17 production by OX40/OX40L interaction.
abstract: The T-cell cytokine IL-17 is implicated in multiple inflammatory diseases through its induction of several pro-inflammatory cytokines and chemokines in a broad range of cell targets. Production of IL-17 defines the Th17 subset of helper T-cells associated with protection against microorganisms, a profile best characterized in the murine system. Multiple regulators of Th17 cell differentiation and IL-17 production are reported, but the impact of OX40L is not described. OX40 ligand (OX40L) is an early-stage activator of T-cells through its interaction with CD134 (OX40) that is up-regulated on antigen challenged T-cells. Here, we show that OX40L suppresses IL-17 production by PHA-stimulated human PBMC and purified CD4 and CD8 cells. In agreement with prior reports, OX40L signaling through CD134 increased IFNgamma and IL-4, both of which are reported to inhibit the production of IL-17. OX40L suppression of IL-17 was completely reversed by a neutralizing IFNgamma antibody while there was no effect with a neutralizing IL-4 antibody. Moreover, OX40L also suppressed IL-17 in the presence of IL-23, an established inducer of IL-17 and differentiation factor for Th17 cells. Presuming mediation by IFNgamma, we evaluated expression of this cytokine in the presence of OX40L and IL-23. Surprisingly, IL-23 also induced IFNgamma by PHA-stimulated T-cells and this effect was enhanced in the presence of OX40L. Addition of the IFNgamma antibody not only reversed the OX40L suppression of IL-17 in the presence of IL-23, it markedly enhanced the level of IL-17. These results further establish IFNgamma as a primary modulator of IL-17 production in the human cells, much as in the murine system.
authors.affiliation: Centocor Inc., 200 Great Valley Parkway, Malvern, PA 19355, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Xiaozhou
authors.initials: X
authors.lastname: Shang
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Benson
authors.forename: M
authors.initials: M
authors.lastname: Merle Elloso
authors.forename: Allen
authors.initials: A
authors.lastname: Schantz
authors.forename: Michelle
authors.initials: M
authors.lastname: Bracht
authors.forename: Yevgeniya
authors.initials: Y
authors.lastname: Orlovsky
authors.forename: Ray
authors.initials: R
authors.lastname: Sweet
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology*; D053759:Interleukin-23 / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D051379:Mice; D053278:OX40 Ligand / Q000276:immunology*; D010835:Phytohemagglutinins / Q000276:immunology; D053262:Receptors, OX40 / Q000276:immunology*
chemical_list: D020381:Interleukin-17; D053759:Interleukin-23; D015850:Interleukin-6; D053278:OX40 Ligand; D010835:Phytohemagglutinins; D053262:Receptors, OX40; D015847:Interleukin-4; D007371:Interferon-gamma