Granulocytes are critical components of the innate immune system whose lifespan is limited by an intrinsic, constitutive, apoptotic pathway. However, the lifespan of these cells can be extended at an inflammatory locus through interaction with survival factors. Although a wide variety of factors can modulate granulocyte survival, they often utilize a common subset of intracellular signal transduction pathways. Over the last decade, evidence has accumulated that the PI3K (phosphatidylinositol 3-kinase) family of lipid kinases may be critical in regulating the ability of granulocytes to survive at inflammatory loci. Studies utilizing both pharmacological inhibitors of PI3K and isoform-specific knockout mice have demonstrated that this enzyme is needed for the anti-apoptotic effects of granulocyte survival factors. More recently, a serine/threonine protein kinase, termed protein kinase B (also known as c-akt), has been demonstrated to be important in modulating the prosurvival effects of PI3K activation. This can occur through modulation of the expression or phosphorylation of members of the Bcl-2 (B-cell lymphocytic-leukaemia proto-oncogene 2) family of apoptosis regulators. This review summarizes recent results that have implicated a role for PI3K in regulating granulocyte survival.
Abbreviations used: Bcl-2, B-cell lymphocytic-leukaemia proto-oncogene 2; fMLP, N-formylmethionyl-leucylphenylalanine; FOXO, forkhead box, class O; GM-CSF, granulocyte/macrophage colony-stimulating factor; GPCR, G-protein-coupled receptor; IFN, interferon; NF-κB, nuclear factor κB; IκB, inhibitor of NF-κB; PDK, phosphoinositide-dependent kinases; PI3K, phosphatidylinositol 3-kinase; PKB, protein kinase B; PKC, protein kinase C.
Apoptosis in Myeloid Cells: Molecular Insights into Disease Processes: a Biochemical Society Focused Meeting held at New Edinburgh Royal Infirmary, Little France, Nr. Edinburgh, 19–20 November 2003