Disease relevance of ELA2

• Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2 [1].
• This study underlines the importance of ELA2 molecular screening to identify patients who may be at particular risk of severe bacterial infections and/or acute myeloid leukemia/myelodysplasia [2].
• Haplotype analysis indicated an overall strong association between the two ELA2 markers and lung cancer risk [3].
• Neutrophil elastase in respiratory epithelial lining fluid of individuals with cystic fibrosis induces interleukin-8 gene expression in a human bronchial epithelial cell line [4].
• There is evidence to suggest that neutrophil elastase (NE) released by neutrophils on the respiratory epithelial surface plays a major role in the pathogenesis of this lung disease [5].

Psychiatry related information on ELA2

• Protein adducts of the lipid peroxidation product trans-4-hydroxy-2-nonenal (HNE) are features of oxidative damage in neuronal cell bodies in Alzheimer's disease but are also seen in axons of normal as well as diseased individuals [6].
• With the exception of rare immunoreactive Pick bodies in one case of Pick's disease, no other structure was recognized by HNE pyrrole adduct antiserum in this series of patients [7].
• The mean PMN elastase levels, determined by immunoactivation method, in patients with major depression without and with melancholia, dysthymia and healthy subjects were found to be 99.5 (10.8) microgram(s)/L [arithmetic mean (SEM)], 289.0 (71.3) microgram(s)/L, 55.7(5.5) microgram(s)/L, and (47.3(2.6) microgram(s)/L, respectively [8].
• The Swedish Enuresis Trial (SWEET) was conducted to evaluate the long-term safety and efficacy of intranasal desmopressin treatment in children with primary, monosymptomatic nocturnal enuresis (PMNE) [9].
• CONCLUSION: These findings suggest that PMNE activity is a state dependent parameter and improvement of depressive symptoms due to antidepressant treatment may lead to decrement of PMNE levels [10].

High impact information on ELA2

• We show by chromatin immunoprecipitation, gel shift, reporter assays and elevated expression of ELA2 in vivo in neutropenic individuals that GFI1 represses ELA2, linking these two genes in a common pathway involved in myeloid differentiation [1].
• The similar autosomal recessive disease of dogs, canine cyclic hematopoiesis, is not caused by mutations in ELA2 (data not shown) [11].
• C-terminal processing of neutrophil elastase exposes an AP3 interaction signal responsible for redirecting neutrophil elastase trafficking from membranes to granules [11].
• Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis [12].
• Neutrophil elastase (a 240-aa mature protein predominantly found in neutrophil granules) is the target for protease inhibition by alpha1-antitrypsin, and its unopposed release destroys tissue at sites of inflammation [12].

Chemical compound and disease context of ELA2

• Mutations in ELA2, encoding the human serine protease neutrophil elastase, cause cyclic and severe congenital neutropenia, and recent evidence indicates that the mutations alter the membrane trafficking of neutrophil elastase [13].
• Antineutrophil cytoplasmic antibodies reacting with human neutrophil elastase as a diagnostic marker for cocaine-induced midline destructive lesions but not autoimmune vasculitis [14].
• BACKGROUND: Matrix degradation in emphysema has long been attributed to the action of neutrophil elastase (NE) [15].
• In conclusion, interleukin-8, neutrophil elastase and leukotriene B4 contribute to the neutrophilic inflammation in the airways of chronic lower respiratory tract infection patients and the clinical effects of roxithromycin may, in part, be attributable to the suppression of excess release of the chemotactic mediators from inflammatory cells [16].
• A neutrophil elastase inhibitor, sivelestat, ameliorates lung injury after hemorrhagic shock in rats [17].

Biological context of ELA2

• Therefore, the current study investigated whether mutations in ELA2 could account for the disease phenotype in classical autosomal recessive SCN and in the sporadic and autosomal dominant types [18].
• All 5 exons of ELA2 and their flanking introns were studied in 18 patients (3 autosomal recessive, 5 autosomal dominant [from 3 kindreds], and 10 sporadic) using direct automated sequencing [18].
• The altered chromatin structure specific to cells that actively transcribe the AZU1-PRTN3-ELA2 genes suggests that chromatin reorganization is an important mechanism regulating the myeloid-specific transcription of this gene cluster [19].
• Neutrophil elastase-2 (ELA2), encoding neutrophil elastase, was typed by two single-nucleotide polymorphism sites [3].
• Mutations in the ELA2 gene, which encodes for neutrophil elastase, cause cyclic hematopoiesis [20].

Anatomical context of ELA2

• Mutational analysis was performed by sequencing polymerase chain reaction (PCR)-amplified genomic DNA for each of the 5 exons of the neutrophil ELA2 gene and 20 bases of the flanking regions [21].
• We then examined the changes in chromatin structure at the locus which accompany myeloid cell differentiation and identified 17 DNase I hypersensitive sites (DHS 1 to 17) in U-937 cells, an early myelomonocytic cell line expressing high levels of neutrophil elastase [19].
• Changes in chromatin organization at the neutrophil elastase locus associated with myeloid cell differentiation [19].
• Our results indicate that whole-cell extracts of monocytes contain approximately 6% of the amount of HLE as do extracts of comparable numbers of PMN [22].
• Elafin overexpression protected endothelial cells from HNE-induced IL-8 production and cytotoxicity [23].

Associations of ELA2 with chemical compounds

• The five exons of AZU and PR3 are organized like those of NE and other granule-associated serine proteases of hematopoietic cells [24].
• Although preincubation of ECs with HLE or Cat G prevented cytosolic calcium mobilization and prostacyclin synthesis induced by thrombin, these cell responses were not affected when triggered by TRAP42-55, a synthetic peptide corresponding to the sequence of the tethered ligand (Ser42-Phe55) unmasked by thrombin on cleavage of its receptor [25].
• Neutrophil elastase inactivated with phenylmethylsulfonyl fluoride did not compete with active elastase for binding to thrombospondin, implying that a functional active site is important for the interaction of elastase with thrombospondin [26].
• Treatment with trypsin, an agonist for PAR-2, and a synthetic PAR-2 agonist peptide induced intracellular Ca(2+) mobilization and rendered cells refractory to subsequent stimulation with HLE and Cat G [27].
• HNE-stimulated secretion involved activation of protein kinase C (PKC), as HNE exposure rapidly provoked PKC enzymatic activity that was attenuated by the general PKC inhibitors calphostin C and bisindoylmaleimide I [28].

Physical interactions of ELA2

• Thrombospondin is a tight-binding competitive inhibitor of neutrophil elastase [26].
• In conclusion, macrophages release a factor or factors, probably lipid, which can interact with NE and inhibit its binding to human lung elastin without inhibiting elastase activity [29].
• Western blot analysis showed that this murine muscle-secreted human AAT (hAAT) formed a complex with human neutrophil elastase in a dose-dependent manner [30].
• These results indicate the increase in MUC1 gene transcription by NE is mediated through increase in Sp1 binding to -99/-90 segment of MUC1 promoter [31].
• Noncovalent complexes between HLE and either the tight-binding secretory leucoprotease inhibitor (SLPI) or a slow tight-binding peptide difluoroketone inhibitor were not observed by ESI-MS [32].

Enzymatic interactions of ELA2

• Thrombospondin was cleaved by neutrophil elastase, but the site(s) of the limited cleavage are independent of the competitive inhibition of elastase activity by thrombospondin [26].
• Human leukocyte elastase (HLE) hydrolysed baboon aortic elastin 8 times faster than human cathepsin G [33].
• HNE cleaved active PAI-1 and produced low molecular weight forms of inactive PAI-1, as previously reported [34].
• Neutrophil elastase rapidly cleaved TFPI at the Thr87-Thr88 bond situated at the link between Kunitz domains I and II [35].
• Human factor V (FV) can be cleaved by HNE thereby providing FV with cofactor activity (FVa(HNE)) [36].

Co-localisations of ELA2

• Furthermore, myeloperoxidase colocalized with human leukocyte elastase [37].

Regulatory relationships of ELA2

• Human neutrophil elastase (HNE) exists in high concentrations (1-20 microM) in airway secretions of these patients and induces overproduction of MUC5AC mucin, a major component of airway mucus [38].
• We now report that NE downregulates tropoelastin mRNA in the rat fetal lung fibroblast line RFL-6 [39].
• Proper selection of the primary specificity group (R(I)) was found to lead to selective inhibition of HLE over Cat G, however, those compounds that inhibited HLE also inhibited PR 3, albeit less efficiently [40].
• Furthermore, MyD88Delta inhibited NE-induced IRAK degradation [41].
• The direct proteolysis by HLE of the membrane CD14 expressed on monocytes illustrates a potential anti-inflammatory effect of HLE through inhibition of LPS-mediated cell activation [42].

Other interactions of ELA2

• The addition of purified NE caused BET-1A cells to increase IL-8 gene transcription with accumulation of mRNA transcripts and to release IL-8-like neutrophil chemotactic activity [4].
• This finding suggested that the augmented release was attributable to PR3 but not NE nor Cat G [43].
• Neutrophil elastase enzymatically antagonizes the in vitro action of G-CSF: implications for the regulation of granulopoiesis [44].
• Monocyte-derived serine proteinases may participate in extracellular events formerly associated with PMN-derived HLE and CG [22].
• Affinity of binding of neutrophil elastase to thrombospondin was sensitive to ionic strength and calcium ions [26].

Analytical, diagnostic and therapeutic context of ELA2

• Our fluorescence in situ hybridization studies disprove the previous chromosomal assignment of the human NE gene to 11q14 [24].
• Using IIaR-A, a monoclonal antibody directed against the sequence encompassing this cleavage site, flow cytometry analysis showed that the surface expression of this epitope was abolished after incubation of ECs with HLE or Cat G [25].
• Western blot analysis demonstrated that activation of NFkappaB by NE was preceded by phosphorylation and degradation of IkappaB proteins, principally IkappaBbeta [41].
• Electrophoretic mobility shift assays demonstrated that nuclear factor kappaB (NFkappaB) was activated in 16HBE14o(-) cells stimulated with NE [41].
• Inhibition of caspases did not block the cleavage of p65 NF-kappaB, and sequence analysis showed that the PR3 and HNE cleavage sites are unique with respect to reported caspase sites [45].

References