Regulation of granulocyte apoptosis by phosphatidylinositol 3-kinase

Abstract

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.

Phosphatidylinositol 3-kinase and p38 mitogen-activated protein kinase regulate induction of Mcl-1 and survival in glucocorticoid-treated human neutrophils

“…For instance, p38 has been shown to phosphorylate and deactivate caspase-3 and caspase-8, 32 or PI3K-mediated Akt activity can lead to prosurvival phosphorylation of Bad, Bax, and caspase-9. 36,50 Taken together, our observations provide a model in which glucocorticoid-mediated inhibition of primary human neutrophil apoptosis is associated with increased levels of Mcl-1 and XIAP. Upregulation of these molecules correlates with suppression of various downstream pathways of apoptosis.…”

Expression of LGI1 Impairs Proliferation and Survival of HeLa Cells

“…Thus the balance of these apoptotic factors imposed by E6 to sustain cell survival might be destabilized by LGI1 in favor of apoptosis. Although the mechanism of cell death induced by LGI1 has not been completely elucidated, it seems possible that LGI1 might interfere with central survival pathways such as the PI3K/AKT, as it occurred in neuroblastoma cells [13], because the prosurvival effects of this pathway includes transcriptional regulation of BCL2 and BAX genes [30, 31]. …”

Signaling pathways involved in MDSC regulation

“…Moreover, the p110γ deficient neutrophils had high rates of apoptosis under steady state conditions and after LPS treatment. These neutrophils had low levels of Akt and other pro-apoptotic proteins like Bcl2, suggesting a role for p110γ in neutrophil survival in vivo [72];[73]. …”