title: A lack of secretory leukocyte protease inhibitor (SLPI) causes defects in granulocytic differentiation.
abstract: We identified diminished levels of the natural inhibitor of neutrophil elastase (NE), secretory leukocyte protease inhibitor (SLPI), in myeloid cells and plasma of patients with severe congenital neutropenia (CN). We further found that downregulation of SLPI in CD34(+) bone marrow (BM) hematopoietic progenitors from healthy individuals resulted in markedly reduced in vitro myeloid differentiation accompanied by cell-cycle arrest and elevated apoptosis. Reciprocal regulation of SLPI by NE is well documented, and we previously demonstrated diminished NE levels in CN patients. Here, we found that transduction of myeloid cells with wild-type NE or treatment with exogenous NE increased SLPI messenger RNA and protein levels, whereas transduction of mutant forms of NE or inhibition of NE resulted in downregulation of SLPI. An analysis of the mechanisms underlying the diminished myeloid differentiation caused by reduced SLPI levels revealed that downregulation of SLPI with short hairpin RNA (shRNA) upregulated nuclear factor κB levels and reduced phospho-extracellular signal-regulated kinase (ERK1/2)-mediated phosphorylation and activation of the transcription factor lymphoid enhancer-binding factor-1 (LEF-1). Notably, microarray analyses revealed severe defects in signaling cascades regulating the cell cycle, including c-Myc-downstream signaling, in myeloid cells transduced with SLPI shRNA. Taken together, these results indicate that SLPI controls the proliferation, differentiation, and cell cycle of myeloid cells.
authors.affiliation: Department of Molecular Hematopoiesis and.
authors.forename: Olga
authors.initials: O
authors.lastname: Klimenkova
authors.forename: Wienke
authors.initials: W
authors.lastname: Ellerbeck
authors.forename: Maksim
authors.initials: M
authors.lastname: Klimiankou
authors.forename: Murat
authors.initials: M
authors.lastname: Ünalan
authors.forename: Siarhei
authors.initials: S
authors.lastname: Kandabarau
authors.forename: Anna
authors.initials: A
authors.lastname: Gigina
authors.forename: Kais
authors.initials: K
authors.lastname: Hussein
authors.forename: Cornelia
authors.initials: C
authors.lastname: Zeidler
authors.forename: Karl
authors.initials: K
authors.lastname: Welte
authors.forename: Julia
authors.initials: J
authors.lastname: Skokowa
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation / Q000276:immunology; D000080984:Congenital Bone Marrow Failure Syndromes; D005786:Gene Expression Regulation / Q000276:immunology; D006098:Granulocytes / Q000166:cytology* / Q000378:metabolism* / Q000473:pathology*; D057809:HEK293 Cells; D006801:Humans; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000276:immunology; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009503:Neutropenia / Q000151:congenital* / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D053481:Secretory Leukocyte Peptidase Inhibitor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D013234:Stem Cells
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C104759:HAX1 protein, human; D016328:NF-kappa B; D012333:RNA, Messenger; C506814:SLPI protein, human; D053481:Secretory Leukocyte Peptidase Inhibitor; D019272:Leukocyte Elastase