Features | Partner Sites | Information | LinkXpress
Sign In
BioConferenceLive
JIB
GLOBETECH PUBLISHING

Chronic Inflammation Maintained by the Immunosuppressive Action of TNF-alpha

By BiotechDaily International staff writers
Posted on 18 Apr 2013
Researchers studying how the immune system deals with chronic inflammation have found that the cytokine tumor necrosis factor-alpha (TNF-alpha) exhibits a dual function during chronic inflammation that results in the formation of an immunosuppressive environment that supports the continuation of the inflammatory condition.

TNF is primarily produced as a 212-amino acid-long type II transmembrane protein arranged in stable homotrimers. 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


comments powered by Disqus

Channels

Drug Discovery

view channel
Image: Molecular rendering of the crystal structure of parkin (Photo courtesy of Wikimedia Commons).

Cinnamon Feeding Blocks Development of Parkinson's Disease in Mouse Model

A team of neurological researchers has identified a molecular mechanism by which cinnamon acts to protect neurons from damage caused by Parkinson's disease (PD) in a mouse model of the syndrome.... Read more

Therapeutics

view channel

Vaccine Being Developed for Heart Disease Close to Reality

The world’s first vaccine for heart disease is becoming a possibility with researchers demonstrating significant arterial plaque reduction in concept testing in mice. Klaus Ley, MD, from the La Jolla Institute for Allergy and Immunology (LA Jolla, CA, USA), and a vascular immunology specialist, is leading the vaccine... Read more

Business

view channel

A Surge in IPOs Revitalize Investments for the Global Pharma and Biotech

Anti-infective drugs, oncology, and pharmaceutical contract laboratories attract the most investment up to now. The intensified private equity and venture capital (PEVC) deal activity in the global healthcare industry during the recession years, 2008–2010, witnessed a waning post-2010. However, the decline in deals... Read more
 
Copyright © 2000-2014 Globetech Media. All rights reserved.