The Therapeutic Potential for PI3K Inhibitors in Autoimmune Rheumatic Diseases
Edward Banham-Hall1, Menna R Clatworthy2, Klaus Okkenhaug*, 1
Identifiers and Pagination:Year: 2012
Issue: Suppl 2
First Page: 245
Last Page: 258
Publisher ID: TORJ-6-245
Article History:Received Date: 14/7/2011
Revision Received Date: 16/11/2011
Acceptance Date: 20/11/2011
Electronic publication date: 7/9/2012
Collection year: 2012
open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.
The class 1 PI3Ks are lipid kinases with key roles in cell surface receptor-triggered signal transduction pathways. Two isoforms of the catalytic subunits, p110γ and p110δ, are enriched in leucocytes in which they promote activation, cellular growth, proliferation, differentiation and survival through the generation of the second messenger PIP3. Genetic inactivation or pharmaceutical inhibition of these PI3K isoforms in mice result in impaired immune responses and reduced susceptibility to autoimmune and inflammatory conditions. We review the PI3K signal transduction pathways and the effects of inhibition of p110γ and/or p110δ on innate and adaptive immunity. Focusing on rheumatoid arthritis and systemic lupus erythematosus we discuss the preclinical evidence and prospects for small molecule inhibitors of p110γ and/or p110δ in autoimmune disease.