title: Glucocorticoid-Induced Leucine Zipper Is Expressed in Human Neutrophils and Promotes Apoptosis through Mcl-1 Down-Regulation.
abstract: Glucocorticoid-induced leucine zipper (GILZ) is a potent anti-inflammatory protein, the expression of which is mainly induced by glucocorticoids (GCs) in haematopoietic cells. GILZ regulates signal transduction pathways of inflammation and plays a role in cell survival. The objective of this study was to evaluate the expression and mechanisms of action of GILZ in the apoptosis of human neutrophils. GILZ expression was induced by GCs in human neutrophils, enhanced upon phosphatidylinositol 3-kinase inhibition and resulted in apoptosis amplification. We then stably transfected PLB-985 cells with the human gilz gene and differentiated both control and GILZ-overexpressing clones in neutrophil-like cells. GILZ overexpression in PLB-985 cells led to an exacerbated apoptosis, associated with caspase-3, caspase-9 and caspase-8 activations, and a loss of mitochondrial potential, suggesting that GILZ-induced apoptosis used the mitochondrial pathway. The expression of BH3 interacting domain death agonist, Bcl-2 interacting mediator of cell death, annexin-A1 and Bcl-2-associated X was not affected in PLB-985-GILZ clones, but phosphorylation and subsequent proteasomal degradation of myeloid cell leukemia-1 (Mcl-1) were observed. Noteworthy, Mcl-1 phosphorylation was related to a significant and sustained activation of c-Jun N-terminal kinase (JNK) in PLB-985-GILZ clones. These results reveal GILZ to be a new actor in apoptosis regulation in neutrophil-like cells involving JNK and Mcl-1.
authors.affiliation: UMR996 - Inflammation, Chemokines and Immunopathology, Inserm, Universitx00E9; Paris-Sud, Universitx00E9; Paris-Saclay, Chx00E2;tenay-Malabry, France.
authors.forename: Marie-Alix
authors.initials: MA
authors.lastname: Espinasse
authors.forename: Aurélie
authors.initials: A
authors.lastname: Pépin
authors.forename: Pauline
authors.initials: P
authors.lastname: Virault-Rocroy
authors.forename: Natacha
authors.initials: N
authors.lastname: Szely
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chollet-Martin
authors.forename: Marc
authors.initials: M
authors.lastname: Pallardy
authors.forename: Armelle
authors.initials: A
authors.lastname: Biola-Vidamment
mesh_terms: D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000737:chemistry / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014162:Transfection
chemical_list: D005938:Glucocorticoids; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C404226:TSC22D3 protein, human; D014157:Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases; D046988:Proteasome Endopeptidase Complex