Chronic Inflammation Maintained by the Immunosuppressive Action of TNF-alpha

From this membrane-integrated form, the soluble homotrimeric cytokine (sTNF) is released via proteolytic cleavage by the metalloprotease TNF-alpha converting enzyme (TACE). The soluble 51-kDa trimeric sTNF tends to dissociate at concentrations below the nanomolar range, thereby losing its bioactivity. The secreted form of human TNF-alpha takes on a triangular pyramid shape, and weighs around 17 kDa. Both the secreted and the membrane bound forms are biologically active and have both overlapping and distinct biology activities. TNF-alpha is particularly important as a part of the body's inflammatory response and in normal circumstances (where it is released locally in low levels) helps the immune system defeat pathogens. However, when it is systemically released in the blood and in high levels, it can cause severe and life-threatening symptoms, including shock and multiple organ failure.

Investigators at the Hebrew University of Jerusalem (Israel) had shown previously that in the course of chronic inflammation, myeloid derived suppressor cells (MDSCs)—unique immune system cells with suppressive features—were generated in the bone marrow and migrated into various organs and the blood, imposing a general immune suppression. In the current work, they linked the generation of MDSCs to the activity of TNF-alpha.

Results reported in the March 21, 2013, issue of the journal Immunity revealed that in a mouse model TNF-alpha exhibited a dual function during chronic inflammation. It blocked differentiation of immature MDSCs primarily via the S100A8 and S100A9 inflammatory proteins and their corresponding receptor (RAGE) and augmented MDSC suppressive activity. These functions led to in vivo T- and NK-cell dysfunction accompanied by T-cell antigen receptor zeta-chain downregulation. This activity impaired the animals' immune responses as reflected by their inability to respond against invading pathogens or against developing tumors.

However, administration of the drug etanercept (a TNF-alpha 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.

These results provide new insights into the relationship between TNF-alpha and the development of immune suppression during chronic inflammation. They may aid in the generation of better therapeutic strategies against various pathologies involving elevated TNF-alpha and MDSC levels.

Related Links:
Hebrew University of Jerusalem