title: Tumor necrosis factor-α blocks differentiation and enhances suppressive activity of immature myeloid cells during chronic inflammation.
abstract: Elevated concentrations of tumor necrosis factor-α (TNF-α) are detected in pathologies characterized by chronic inflammation. Whether TNF-α plays a role in manipulating the host's immune system toward generating an immunosuppressive milieu, typical of ongoing chronic inflammation, is unclear. Here we showed that TNF-α exhibited a dual function during chronic inflammation: arresting differentiation of immature myeloid-derived suppressor cells (MDSCs) primarily via the S100A8 and S100A9 inflammatory proteins and their corresponding receptor (RAGE) and augmenting MDSC suppressive activity. These functions led to in vivo T and NK cell dysfunction accompanied by T cell antigen receptor ζ chain downregulation. Furthermore, administration of etanercept (TNF-α antagonist) during early chronic inflammatory stages reduced MDSCs' suppressive activity and enhanced their maturation into dendritic cells and macrophages, resulting in the restoration of in vivo immune functions and recovery of ζ chain expression. Thus, TNF has a fundamental role in promoting an immunosuppressive environment generated during chronic inflammation.
authors.affiliation: The Lautenberg Center for General and Tumor Immunology, The Institute for Medical Research Israel-Canada.
authors.forename: Moshe
authors.initials: M
authors.lastname: Sade-Feldman
authors.forename: Julia
authors.initials: J
authors.lastname: Kanterman
authors.forename: Eliran
authors.initials: E
authors.lastname: Ish-Shalom
authors.forename: Mazal
authors.initials: M
authors.lastname: Elnekave
authors.forename: Elad
authors.initials: E
authors.lastname: Horwitz
authors.forename: Michal
authors.initials: M
authors.lastname: Baniyash
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D040501:Calgranulin A / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D040502:Calgranulin B / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D002908:Chronic Disease; D000068800:Etanercept; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology; D015151:Immunoblotting; D007074:Immunoglobulin G / Q000494:pharmacology; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D040501:Calgranulin A; D040502:Calgranulin B; D007074:Immunoglobulin G; D011948:Receptors, Antigen, T-Cell; D018124:Receptors, Tumor Necrosis Factor; C576329:S100A9 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C498977:Mok protein, mouse; D020928:Mitogen-Activated Protein Kinases; D000068800:Etanercept