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. 2012:6:245-58.
doi: 10.2174/1874312901206010245. Epub 2012 Sep 7.

The Therapeutic Potential for PI3K Inhibitors in Autoimmune Rheumatic Diseases

Edward Banham-Hall  1 , Menna R Clatworthy, Klaus Okkenhaug
Affiliations

The Therapeutic Potential for PI3K Inhibitors in Autoimmune Rheumatic Diseases

Edward Banham-Hall et al. Open Rheumatol J. 2012.

Abstract

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.

Keywords: PI3K inhibitors; PI3K.; autoimmunity; humoral immune; pleckstrin homology; rheumatoid arthritis; systemic lupus erythematosus.

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Figures

Fig. (1)
Fig. (1)
p110γ and p110δ are involved in the response to various cell signalling cascades that depend on cell type.
Fig. (2)
Fig. (2)
The production of PIP3 is a critical signalling hub. GPCR's and receptor tyrosine kinases expressing a YxxM motif recruit PI3K to the plasma membrane via interactions with SH2 domains. PI3 kinases then catalyse the formation of PIP3 from PI-4,5-P2. PIP3 then acts on a variety of downstream effectors expressing PH domains to promote cellular responses.
See this image and copyright information in PMC

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