PI3Kδ and PI3Kγ: partners in crime in inflammation in rheumatoid arthritis and beyond?

Phosphoinositide 3-kinases (PI3Ks) generate lipid-based second messengers that control an array of intracellular signalling pathways that are responsible for many cellular functions, such as growth and proliferation, survival and apoptosis, as well as adhesion and migration.Two isoforms of the class I PI3K family, PI3Kδ and PI3Kγ, are mainly expressed by cells of the haematopoietic system, in which they have a crucial role in signalling downstream of numerous receptors, such as cytokine receptors, G-protein-coupled receptors, receptor tyrosine kinases, Toll-like receptors and antigen receptors.Experimental models of immune-based and inflammatory diseases using either gene-modified mice or pharmacological inhibitors of PI3Kδ and PI3Kγ have helped to identify the crucial functions of these PI3K isoforms, indicating that they have important non-redundant roles in mast cells, neutrophils, dendritic cells, B cells and T cells.In some cellular responses, such as the generation of reactive oxygen species by neutrophils and the degranulation by mast cells, both PI3Kδ and PI3Kγ seem to be required. This favours a model in which the contribution of PI3Kδ and PI3Kγ is coordinated at different stages of signalling in these cells.The potential of PI3Kδ and PI3Kγ as drug targets for the intervention of inflammatory and allergic disorders is also addressed.Recent studies are highlighted showing that targeting PI3K isoforms can reduce glomerulonephritis in a mouse model of systemic lupus erythematosus and suppresses the progression of disease in mouse models of rheumatoid arthritis.