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

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By M. Sade-Feldman et al. • • April 6, 2013

Editor's Comment: A number of studies have found elevated inflammatory cytokines in patients with CFS/ME. In 1999, Moss et al. discovered that TNF-a was elevated in CFS patients. Maes et al. confirmed this finding in 2011. Elevated levels of inflammatory cytokines, including TNF-a, have also been found in fibromyalgia patients. (Read the abstract HERE.Zeta chain downregulation has been implicated in cancer and in autoimmune diseases.

~Source: Immunity, Volume 38, Issue 3, 541-554, 07 March 2013

By M. Sade-Feldman et al.


  • TNF-a promotes immunosuppression during chronic inflammation via MDSCs
  • TNF-a blocks MDSC maturation by enhancing S100A8/9 and RAGE expression
  • TNF-a augments MDSC suppressive activity impairing T and NK cell function
  • Etanercept enhances MDSC maturation and reduces their suppressive activity


Elevated concentrations of tumor necrosis factor-a (TNF-a) are detected in pathologies characterized by chronic inflammation. Whether TNF-a 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-a 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 zeta chain downregulation. Furthermore, administration of etanercept (TNF-a 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 zeta chain expression. Thus, TNF has a fundamental role in promoting an immunosuppressive environment generated during chronic inflammation.

Source: Immunity, Volume 38, Issue 3, 541-554, 07 March 2013. Sade-Feldman M, Kanterman J, Ish-Shalom E, Elnekave M, Horwitz E, Baniyash M. The Lautenberg Center for General and Tumor Immunology, The Institute for Medical Research Israel-Canada.

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Article Comments Post a Comment

Posted by: IanH
Apr 6, 2013
Also reduces mitochondrial membrane potential gradient when chronically elevated. This in turn leads to many of the symptoms in ME/CFS
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