Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

Sustained inflammatory responses are central to the development and progression of chronic diseases, including atherosclerosis and rheumatoid arthritis. A large number of stimuli initiate inflammation by acting on Toll-Interleukin-1 related (TIR) domain containing receptors, producing multiple second messengers and thence large scale transcriptional changes. The mechanism by which this activation occurs is complex, and the continuing isolation of novel pathway components, mostly based on sequence similarities and protein-protein interaction studies, suggests that many elements of the TIR-initiated signalling network remain to be identified. Here we use a new technique, allowing identification of components based on function. We report the performance of the screen, our identification of human tribbles as a novel protein family regulating inflammatory signalling networks, and the detection of ten other components with poorly characterized roles in inflammatory signalling pathways. In total, we have identified 28 signalling molecules of diverse molecular mechanism by screening 11% of a cDNA library for the ability to modulation expression of human IL-8, and other molecules remain to be followed up. The results suggest that the number of human genes involved in IL-8 induction pathways exceed 100. The isolation of signalling components by the approach we describe allows detection of new classes of signalling components independent of existing techniques for doing so; it is simple and robust, and constitutes a general method for mapping signal transduction systems controlling gene expression.

Original publication

DOI

10.1016/j.cellsig.2005.04.012

Type

Journal article

Journal

Cell Signal

Publication Date

02/2006

Volume

18

Pages

202 - 214

Keywords

3' Untranslated Regions, Amino Acid Sequence, Cloning, Molecular, Computer Simulation, Gene Expression Regulation, Gene Library, HeLa Cells, Humans, Interleukin-8, Mitogen-Activated Protein Kinases, Molecular Sequence Data, NF-kappa B, Receptors, Interleukin-1, Sequence Alignment, Signal Transduction, Toll-Like Receptors, Transcription Factors, Transcription, Genetic