Neutrophil activation by fMLP regulates FOXO (forkhead) transcription factors by multiple pathways, one of which includes the binding of FOXO to the survival factor Mcl-1

Abstract

Activation signals from bacterial stimuli set into motion a series of events that alter the abbreviated lifespan of neutrophils. These studies show that the bacterial chemoattractant, formyl-Met-Leu-Phe (fMLP), promotes the phosphorylation/inactivation of the FOXO subfamily of forkhead transcription factors (FKHR, FKHR-L1, and AFX) through the phosphatidylinositol-3-kinase/Akt (protein kinase B) and the RAS mitogen-activated protein kinase pathways. Furthermore, fMLP stimulation causes the inducible expression of the prosurvival Bcl-2 family member Mcl-1, which then binds to a complex containing FKHR. These studies show that fMLP-stimulated neutrophils coordinate the regulation of FOXO transcription factors and the survival factor Mcl-1, a mechanism that may allow neutrophils to alter their survival.

Adenovirus-mediated gene transfer of FKHRL1 triple mutant efficiently induces apoptosis in melanoma cells

“…Furthermore, fMLP stimulation caused inducible expression of the prosurvival Bcl-2 family member Mcl-1, which binds to a complex containing FKHR. 54 On the other hand, levels of CREB-dependent anti-apoptotic protein, Mcl-1, and of NFκB-dependent anti-apoptotic mediator, Bcl-x L , were significantly decreased in PI3-Kγ -/-neutrophils. 55 In addition, the expression of the activated form of AFX upregulated Bcl-6, a transcriptional repressor that can repress Bcl-x L , since the promoter of this gene contains potential Bcl-6 target sites.…”

Constitutive neutrophil apoptosis: Mechanisms and regulation

“…Inhibition of NF-kB by its specific inhibitors or a TAT-NEMO-binding domain peptide significantly augments neutrophil apoptosis [71,72]. Phosphorylation and subsequent inactivation of the proapoptotic FOXO subfamily of forkhead transcription factors (FKHR, FKHR-L1, and AFX) is also mediated by the PI3K/Akt pathway [73].…”

Foxo in the immune system

“…In human poylmorphonuclear neutrophils, exposure to the bacterially derived chemoattractant formyl-Met-Leu-Phe results in phosphorylation of Foxo1, Foxo3a and Foxo4, apparently via PI3K and mitogen-activated protein kinase -dependent pathways as judged by pharmacological inhibitors in vitro (Crossley, 2003). Interestingly, formyl-Met-Leu-Phe also induces the Bcl-2-related survival factor Mcl-1, which is capable of forming a complex with Foxo1 and may therefore coordinate neutrophil survival via modulation of Foxo activity.…”

“…Interestingly, enforced expression of an activated (PH domain-deficient) (Crossley, 2003) Abbreviations: CA, constitutively-active mutant; DC, dendritic cell; fMLP, formyl-Met-Leu-Phe; GILZ, glucocorticoid-induced leucine zipper; PMN, polymorphonuclear neutrophil; Rb, retinoblastoma protein; SOD, superoxide dismutase. 'Correlation' indicates an indirect demonstration of the Foxo's involvement, e.g., a correlation between Foxo phosphorylation and p27 Kip1 expression in Vav-deficient T cells (Charvet et al, 2006).…”