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A lack of secretory leukocyte protease inhibitor (SLPI) causes defects in granulocytic differentiation.
- Source :
-
Blood [Blood] 2014 Feb 20; Vol. 123 (8), pp. 1239-49. Date of Electronic Publication: 2013 Dec 18. - Publication Year :
- 2014
-
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.
- Subjects :
- Adaptor Proteins, Signal Transducing genetics
Bone Marrow Cells cytology
Cell Differentiation immunology
Congenital Bone Marrow Failure Syndromes
Gene Expression Regulation immunology
HEK293 Cells
Humans
Leukocyte Elastase antagonists & inhibitors
Leukocyte Elastase genetics
Leukocyte Elastase metabolism
MAP Kinase Signaling System immunology
Myeloid Cells cytology
Myeloid Cells metabolism
NF-kappa B metabolism
Neutropenia metabolism
Neutropenia pathology
Oligonucleotide Array Sequence Analysis
RNA, Messenger metabolism
Secretory Leukocyte Peptidase Inhibitor genetics
Secretory Leukocyte Peptidase Inhibitor immunology
Stem Cells
Granulocytes cytology
Granulocytes metabolism
Granulocytes pathology
Neutropenia congenital
Secretory Leukocyte Peptidase Inhibitor metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 123
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 24352879
- Full Text :
- https://doi.org/10.1182/blood-2013-06-508887