Secretory leukocyte protease inhibitor inhibits neutrophil apoptosis

Subramaniyam, Devipriya; Hollander, Camilla; Westin, Ulla; Erjefält, Jonas; Stevens, Tim; Janciauskiene, Sabina

doi:10.1111/j.1440-1843.2010.01901.x

Cited by 30 publications

(18 citation statements)

References 42 publications

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“…46,47 High levels of SLPI have been demonstrated in cancer cells, including ovarian cancer, gastric cancer, and oral squamous cell carcinoma, 46,48 and SLPI is involved in the proliferation 48-50 and survival of tumor cells and neutrophils. 30,31 Consistent with this, myeloid cells of SLPI-deficient CN patients exhibit cell-cycle arrest and elevated apoptosis. [11][12][13][14] Some of the activities of SLPI are independent of its protease inhibitory activity.…”

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confidence: 58%

“…29 SLPI also exhibits antiapoptotic activity through binding to annexin II on the cell surface 30 and has been shown to protect granulocytes from apoptosis. 31 Intriguingly, SLPI is also known to modulate intracellular signal transduction pathways, such as nuclear factor kB (NF-kB) and extracellular signal-regulated kinase (ERK). [32][33][34] In this latter context, it has been shown that SLPI is involved in the activation (phosphorylation) of ERK1/2 protein, 33 which plays an important role in G-CSF-triggered myeloid differentiation.…”

Section: Introductionmentioning

confidence: 99%

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A lack of secretory leukocyte protease inhibitor (SLPI) causes defects in granulocytic differentiation

Klimenkova¹,

Ellerbeck²,

Klimiankou³

et al. 2014

Blood

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Key Points• The natural inhibitor of neutrophil elastase, SLPI, is severely reduced in severe congenital neutropenia patients.• SLPI controls myeloid differentiation by regulation of NFkB, ERK1/2:LEF-1, and c-myc activation.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 1 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 kB 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. (Blood. 2014;123(8):1239-1249

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confidence: 58%

Section: Introductionmentioning

confidence: 99%

A lack of secretory leukocyte protease inhibitor (SLPI) causes defects in granulocytic differentiation

Klimenkova¹,

Ellerbeck²,

Klimiankou³

et al. 2014

Blood

View full text Add to dashboard Cite

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“…Interestingly, when we considered up-regulated genes in this enriched group separately, the innate immune response in particular was featured. For example, Secretory Leukocyte Peptidase Inhibitor (SLPI) and Azurocidin 1 (AZU1) are chemotactic for cells of the innate immune system and modulate the inflammatory response (Sallenave, 2002;Soehnlein et al, 2008;Subramaniyam et al, 2011). Lipocalin 2 (LCN2) is up-regulated during inflammation and in the plasma of patients with mild cognitive impairment (Choi et al, 2011), and is induced by IL-1b, a protein elevated in the CSF of first episode schizophrenia patients (Cowland et al, 2003;Soderlund et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Gene expression analysis reveals schizophrenia-associated dysregulation of immune pathways in peripheral blood mononuclear cells

Gardiner

Cairns

Liu

et al. 2013

Journal of Psychiatric Research

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Peripheral blood mononuclear cells (PBMCs) represent an accessible tissue source for gene expression profiling in schizophrenia that could provide insight into the molecular basis of the disorder. This study used the Illumina HT_12 microarray platform and quantitative real time PCR (QPCR) to perform mRNA expression profiling on 114 patients with schizophrenia or schizoaffective disorder and 80 non-psychiatric controls from the Australian Schizophrenia Research Bank (ASRB). Differential expression analysis revealed altered expression of 164 genes (59 up-regulated and 105 down-regulated) in the PBMCs from patients with schizophrenia compared to controls. Bioinformatic analysis indicated significant enrichment of differentially expressed genes known to be involved or associated with immune function and regulating the immune response. The differential expression of 6 genes, EIF2C2 (Ago 2), MEF2D, EVL, PI3, S100A12 and DEFA4 was confirmed by QPCR. Genome-wide expression analysis of PBMCs from individuals with schizophrenia was characterized by the alteration of genes with immune system function, supporting the hypothesis that the disorder has a significant immunological component in its etiology.

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“…The role of elastase in neutrophil apoptosis has been considered, and a recent study demonstrated that the secretory leukocyte protease inhibitor SLP1 could inhibit neutrophil apoptosis [37]. Upon PMA activation and ROS production, neutrophil-derived elastase translocates to the nucleus and aids in chromatin decondensation leading to NETosis [28].…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosis-Induced Neutrophil Extracellular Traps Activate Human Macrophages

Braian

Hogea

Stendahl³

2013

J Innate Immun

130

159

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Neutrophils activated by Mycobacterium tuberculosis (Mtb) form neutrophil extracellular traps (NETs), containing DNA and several biologically active cytosolic and granular proteins. These NETs may assist in the innate immune defense against different pathogens. We investigated whether the NET-forming neutrophils mediate an activating signal to macrophages during the early multicellular inflammatory reaction and granuloma formation. Mtb-induced NETs were found to be reactive oxygen species dependent and phagocytosis dependent. A neutrophil elastase inhibitor also delayed NET formation. However, NET formation occurred independently of Mtb-induced apoptosis. We observed close interactions between macrophages and Mtb-activated neutrophils, where macrophages bound and phagocytosed NETs. Significant secretion of the cytokines interleukin (IL)-6, tumor necrosis factor-α, IL-1β and IL-10 were detected from macrophages cocultured with NETs from Mtb-activated but not phorbol myristate acetate-activated neutrophils. NETs binding heat shock protein 72 (Hsp72) or recombinant Hsp72 were able to trigger cytokine release from macrophages. Only Mtb-induced NETs contained Hsp72, suggesting that these NETs can transfer this danger signal to adjacent macrophages. We propose that Hsp72 sequestered in NETs plays an important role in the interaction between neutrophils and macrophages during the early innate immune phase of an Mtb infection. The immunomodulatory role of NETs and proteins derived from them may influence not only chronic inflammation during tuberculosis but also immune regulation and autoimmunity.

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Secretory leukocyte protease inhibitor inhibits neutrophil apoptosis

Abstract: Our findings indicate upregulation of SLPI in response to LPS in nasal secretions and show anti-apoptotic effects of SLPI in primary human neutrophils suggesting a new role of SLPI during neutrophilic inflammation.

Cited by 30 publications

References 42 publications

A lack of secretory leukocyte protease inhibitor (SLPI) causes defects in granulocytic differentiation

A lack of secretory leukocyte protease inhibitor (SLPI) causes defects in granulocytic differentiation

Gene expression analysis reveals schizophrenia-associated dysregulation of immune pathways in peripheral blood mononuclear cells

Mycobacterium tuberculosis-Induced Neutrophil Extracellular Traps Activate Human Macrophages

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