Discovery of a new signaling mechanism may lead to novel anti-inflammatory therapy

July 17, 2008

A team of researchers at the University of California, San Diego School of Medicine has uncovered a new signaling mechanism used to activate protein kinases that are critical for the body's inflammatory response. Their work will be published in the July 18 online edition of Science (Science Express.).

"In addition to helping explain the basic mechanisms of transmembrane receptor signaling, these results may identify a potential therapy for interfering with inflammation," said Michael Karin, Ph.D., professor of pharmacology and pathology in UC San Diego's Laboratory of Gene Regulation and Signal Transduction.

The tumor necrosis factor (TNF) receptor (TNFR) family codes for a large number of cell surface receptors of great biomedical importance, and its signaling mechanisms have been the subject of intense investigation during the past decade. Specific inhibitors of TNF receptor 1 (TNFR1) activation are being used in the treatment of rheumatoid arthritis, psoriasis and inflammatory bowel disease, and receptor activator of NF-κB (RANK) inhibitors were recently found to be effective in the treatment of osteoporosis and other bone loss diseases.

Now Atsushi Matsuzawa, Ph.D., and Ping-Hui Tseng, Ph.D., postdoctoral fellows in the Karin laboratory, describe how engagement of CD40, a member of the TNFR family, results in assembly of multiprotein signaling complexes at the receptor. However, according to the researchers - and contrary to previous expectations - signaling cascades that lead to activation of Jun Kinases (JNK) and p38 MAP Kinases (MAPK) are not initiated until these complexes dissociate from the receptor.

The authors found that complex translocation from the cell surface receptor to the cytoplasm, which is required for JNK and p38 activation, depends on degradation of a signaling protein called TRAF3. This process can be inhibited by a class of compounds known as Smac mimics.

"As Smac mimic compounds do not interfere with the activation of NF-κB-dependent innate immunity but do prevent the induction of JNK- and p38- dependent inflammatory mediators, they may serve as the prototypes for new anti-inflammatory therapy," said Karin, who also noted that current drugs that work by interfering with TNFR signaling exceed $5 billion a year in revenue.
-end-
Additional contributors include Sivakumar Vallabhapurapu, Jun-Li Luo and Weizhou Zhang, Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, UCSD School of Medicine; Haopeng Wang and Dario A. A. Vignali, Department of Immunology, St. Jude Children's Research Hospital, Memphis; and Ewen Gallagher, Department of Immunology, Imperial College, London, Faculty of Medicine, Norfolk Place, London. Work was supported by grants from the National Institutes of Health, the Leukemia and Lymphoma Society, The Mochida Memorial Foundation for Medical and Pharmaceutical Research, American Lung Association of California and Life Science Foundation; a Cancer Center Support CORE grant and the American Lebanese Syrian Associated Charities (ALSAC.). Karin is an American Cancer Society Research Professor.

University of California - San Diego

Related Inflammatory Response Articles from Brightsurf:

Inflammatory gene provides clue to obesity risk
A gene that helps to control inflammation increases the risk of obesity and could be turned off in mice to stop weight gain, a study from The University of Queensland has found.

Computational gene study suggests new pathway for COVID-19 inflammatory response
A team led by Dan Jacobson of the Department of Energy's Oak Ridge National Laboratory used the Summit supercomputer at ORNL to analyze genes from cells in the lung fluid of nine COVID-19 patients compared with 40 control patients.

Clues to COVID-19 complications come from NET-like inflammatory response
An overactive defense response may lead to increased blood clotting, disease severity, and death from COVID-19.

3-D shape of human genome essential for robust inflammatory response
The three-dimensional structure of the human genome is essential for providing a rapid and robust inflammatory response but is surprisingly not vital for reprogramming one cell type into another.

New effective treatment for inflammatory diseases found
New research conducted by the University of Liverpool and AKL Research and Development Ltd (AKLRD), published in Inflammopharmacology, highlights the potential benefits of a new drug treatment on the human body's immune response in inflammation.

Electronic cigarettes trigger an inflammatory response that may set the stage for gum disease
The oral microbiomes of 25 otherwise healthy participants who use e-cigarettes daily closely match those seen in patients with gum disease, a new study shows.

A new strategy for the management of inflammatory pain
A group of researchers from Charité - Universitätsmedizin Berlin has discovered a new mechanism of long-lasting pain relief.

A vaccine against chronic inflammatory diseases
In animals, a vaccine modifying the composition and function of the gut microbiota provides protection against the onset of chronic inflammatory bowel diseases and certain metabolic disorders, such as diabetes and obesity.

Inflammatory marker linked to dementia
Higher levels of an inflammatory marker, sCD14, were associated with brain atrophy, cognitive decline and dementia in two large heart studies.

Are steroids used too much for patients with inflammatory bowel disease?
Steroid therapy is commonly used to treat acute attacks of the inflammatory bowel diseases ulcerative colitis and Crohn's disease; however, because it does not provide long-term benefits and it carries a risk of serious side effects, it should not be used to treat inflammatory bowel disease for more than three months.

Read More: Inflammatory Response News and Inflammatory Response Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.