Features Partner Sites Information LinkXpress
Sign In
Advertise with Us
RANDOX LABORATORIES

Chronic Inflammation Maintained by the Immunosuppressive Action of TNF-alpha

By BiotechDaily International staff writers
Posted on 18 Apr 2013
Print article
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


Print article

Channels

Drug Discovery

view channel
Image: A scanning electron microscope (SEM) image of methicillin-resistant Staphylococcus aureus bacteria (Photo courtesy of the CDC).

Drug Combination Cures MRSA Infection While Preventing Development of Resistance

Treatment with a combination comprising the well-known antibiotic cefdinir and the experimental drug TXA709 cured mice of drug-resistant staphylococcal infections while reducing the development of resistance.... Read more

Biochemistry

view channel
Image: A space-filling model of the anticonvulsant drug carbamazepine (Photo courtesy of Wikimedia Commons).

Wastewater May Contaminate Crops with Potentially Dangerous Pharmaceuticals

Reclaimed wastewater used to irrigate crops is contaminated with pharmaceutical residues that can be detected in the urine of those who consumed such produce. Investigators at the Hebrew University... Read more

Lab Technologies

view channel
Image: A three-dimensional printer adapted for stem cell production (Photo courtesy of Nano Dimension).

Israeli Developers Demonstrate Prototype Three-Dimensional Bioprinter

Two Israeli companies have combined efforts in the development of three-dimensional printer technology for the production of stem cells. The three-dimensional print electronics developer Nano Dimension... Read more

Business

view channel

Acquisition to Boost Development of Drugs for Neurogenic Conditions

According to a recent announcement, a privately held biotechnology/drug development company is to be acquired by one of the major pharmaceutical manufacturers. The drug manufacturer Merck & Co. (Kenilworth, NJ, USA) has agreed to pay 500 million USD up front for Afferent Pharmaceuticals (San Mateo, CA, USA) and up... Read more
Copyright © 2000-2016 Globetech Media. All rights reserved.