title: TL1A induces TCR independent IL-6 and TNF-α production and growth of PLZF⁺ leukocytes.
abstract: An elevated level of the cytokine TL1A is known to be associated with several autoimmune diseases, e.g. rheumatoid arthritis and inflammatory bowel disease. However, the mode of action of TL1A remains elusive. In this study, we investigated the role of TL1A in a pro-inflammatory setting, using human leukocytes purified from healthy donors. We show that TL1A, together with IL-12, IL-15 and IL-18, directly induces the production of IL-6 and TNF-α from leukocytes. Interestingly, TL1A-induced IL-6 was not produced by CD14⁺ monocytes. We further show that the produced IL-6 is fully functional, as measured by its ability to signal through the IL-6 receptor, and that the induction of IL-6 is independent of TCR stimulation. Furthermore, the transcription factor PLZF was induced in stimulated cells. These results offer a substantial explanation for the role of TL1A, since TNF-α and IL-6 are directly responsible for much of the inflammatory state in many autoimmune diseases. Our study suggests that TL1A is a possible target for the treatment of autoimmune diseases.
authors.affiliation: Laboratory of Immunology, Faculty of Medical and Health Sciences, University of Copenhagen, Frederiksberg C, Denmark.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Reichwald
authors.affiliation: Laboratory of Immunology, Faculty of Medical and Health Sciences, University of Copenhagen, Frederiksberg C, Denmark.
authors.forename: Tina Z
authors.initials: TZ
authors.lastname: Jørgensen
authors.affiliation: Laboratory of Immunology, Faculty of Medical and Health Sciences, University of Copenhagen, Frederiksberg C, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Tougaard
authors.affiliation: Laboratory of Immunology, Faculty of Medical and Health Sciences, University of Copenhagen, Frederiksberg C, Denmark.
authors.forename: Søren
authors.initials: S
authors.lastname: Skov
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis*; D042541:Intracellular Space / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D007962:Leukocytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D011948:Receptors, Antigen, T-Cell; D013194:Staining and Labeling; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D018836:Inflammation Mediators; D015850:Interleukin-6; D051741:Kruppel-Like Transcription Factors; D018950:Lipopolysaccharide Receptors; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D011948:Receptors, Antigen, T-Cell; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; D014409:Tumor Necrosis Factor-alpha; C092037:ZBTB16 protein, human