PI3K isoforms as drug targets in inflammatory diseases: lessons from pharmacological and genetic strategies.
Inflammation protects the body against infection and injury, but it is a process that can become dysregulated with deleterious consequences, including the development of rheumatoid arthritis, inflammatory bowel disease, psoriasis and multiple sclerosis. In recent years, inflammation has also been demonstrated to play a key role in other widely prevalent diseases not previously considered to have inflammatory etiologies, such as Alzheimer's disease, cardiovascular diseases and cancer. The current anti-inflammatory therapies such as steroids, NSAIDs and antihistamines are mainly based on inhibiting the synthesis or action of inflammatory mediators. The more recently developed biopharmaceuticals (eg, TNFalpha-neutralizing therapies, and anti-IgE and anti-CD20 antibodies) follow a similar therapeutic strategy. However, both the established anti-inflammatory therapies and the more recent biopharmaceutical innovations have shortcomings and there remains a need for the identification and validation of new anti-inflammatory drug targets. This review focuses on the description of the data indicating that PI3K isoforms control inflammation at many levels, from the generation of inflammatory cells to the migration and function of these cells. More specifically, the contribution of the gamma and delta isoforms of PI3K to the immune processes that underpin inflammatory responses, as well as their potential as therapeutic targets, are evaluated.
Harris
Stephanie J
SJ
Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, UK.
Foster
John G
JG
Ward
Stephen G
SG
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000276:immunology / Q000494:pharmacology*; D002465:Cell Movement / Q000502:physiology; D058534:Class I Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; D016503:Drug Delivery Systems; D018390:Gene Targeting / Q000379:methods; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D007527:Isoenzymes / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*
D000893:Anti-Inflammatory Agents; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; C486018:PIK3CD protein, human; C546760:PIK3CG protein, human