Abstract

Cytokines and their Signalling Pathways as Therapeutic Targets in Drug Discovery for Inflammatory Disorders: Focus on Atherosclerosis

Dipak Ramji, Professor, Cardiff University

Cytokines play crucial roles in the control of immune and inflammatory responses. Abnormalities in cytokines, their receptors and the downstream signalling they initiate are associated with a number of inflammatory disorders, including rheumatoid arthritis, inflammatory bowel disease and atherosclerosis. Approaches to limit the actions of pro-inflammatory cytokines include neutralization (blocking antibodies or decoy receptors), receptor antagonists and small molecule inhibitors of intracellular signal transduction pathways. Other avenues include use of anti-inflammatory cytokines or agents that augment their expression/actions. A more thorough understanding of cytokine actions in disease, particularly signalling pathways, is essential for the identification of new therapeutic targets/approaches. The major focus of research in my laboratory has been on cytokine actions and signalling in atherosclerosis. Atherosclerosis, the underlying cause of heart attacks and stroke, is an inflammatory disorder of medium and large arteries and is responsible for most deaths worldwide. Cytokines such as interferon-? and interleukin (IL)-1ß promote atherosclerosis whereas others, particularly IL-10, IL-33 and transforming growth factor-ß, attenuate the disease. Our research has provided novel insights into intracellular signalling pathways and molecular mechanisms underlying the actions of such cytokines, particularly in macrophages in atherosclerosis. These will be presented in the context of current therapies and future drug discovery and development. Interesting, many conventional therapies, such as statins and nutraceuticals, also modulate cytokine signalling and these will be also discussed. Finally, the limitation of cytokine therapeutics and the possibility of approaches involving modulation of cells that produce anti-atherogenic cytokines will be presented.