Tumor Necrosis Factor-[alpha] Blocks Differentiation and Enhances Suppressive Activity of Immature Myeloid Cells during Chronic Inflammation

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. H...

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Bibliographic Details
Published in:Immunity (Cambridge, Mass.) Mass.), 2013-03, Vol.38 (3), p.541
Main Authors: Sade-Feldman, Moshe, Kanterman, Julia, Ish-Shalom, Eliran, Elnekave, Mazal, Horwitz, Elad, Baniyash, Michal
Format: Article
Language:English
Subjects:
Cancer
Cytokines
Flow cytometry
Hypotheses
Immune system
Medical research
R&D
Research & development
Rheumatoid arthritis
Spleen
Statistical analysis
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Summary: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.
ISSN:1074-7613
1097-4180
DOI:10.1016/j.immuni.2013.02.007