title: Tumor-derived macrophage migration inhibitory factor (MIF) inhibits T lymphocyte activation.
abstract: Macrophage migration inhibitory factor (MIF) is a multi-functional cytokine that is considered a pro-inflammatory cytokine. However, our studies show that MIF, when produced in super-physiological levels by a murine neuroblastoma cell line (Neuro-2a) exceeding those normally seen during an immune response, inhibits cytokine-, CD3-, and allo-induced T-cell activation. MIF is also able to inhibit T cells that have already received an activation signal. The T-cell inhibitory effects of culture supernatants from neuroblastoma cells were reversed when the cells were transfected with dicer-generated si-RNA to MIF. When T cells were activated in vitro by co-culture with interleukin (IL)-2 and IL-15 and analyzed for cytokine production in the presence or absence of MIF-containing culture supernatant, inhibition of T-cell proliferation and induced cell death were observed even as the treated T cells produced high levels of interferon-gamma (IFN-gamma). The inhibitory effects of MIF were partially reversed when lymphocytes from IFN-gamma knockout mice were tested. We propose that the high levels of MIF produced by neuroblastoma cause activation induced T-cell death through an IFN-gamma pathway and may eliminate activated T cells from the tumor microenvironment and thus contribute to escape from immune surveillance.
authors.affiliation: Department of Pediatrics, Section of Hematology-Oncology, MFRC 6011, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: Xiaocai
authors.initials: X
authors.lastname: Yan
authors.forename: Rimas J
authors.initials: RJ
authors.lastname: Orentas
authors.forename: Bryon D
authors.initials: BD
authors.lastname: Johnson
mesh_terms: D000818:Animals; D016923:Cell Death; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D019409:Interleukin-15 / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D008213:Lymphocyte Activation; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009369:Neoplasms / Q000276:immunology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*
chemical_list: D019409:Interleukin-15; D007376:Interleukin-2; D008263:Macrophage Migration-Inhibitory Factors; D034741:RNA, Small Interfering; D007371:Interferon-gamma