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ELANE  -  elastase, neutrophil expressed

Homo sapiens

Synonyms: Bone marrow serine protease, ELA2, Elastase-2, GE, HLE, ...
 
 
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Disease relevance of ELA2

 

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

 

Chemical compound and disease context of ELA2

 

Biological context of ELA2

 

Anatomical context of ELA2

 

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

 

Co-localisations of ELA2

 

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

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  2. Mutations in the ELA2 gene correlate with more severe expression of neutropenia: a study of 81 patients from the French Neutropenia Register. Bellanné-Chantelot, C., Clauin, S., Leblanc, T., Cassinat, B., Rodrigues-Lima, F., Beaufils, S., Vaury, C., Barkaoui, M., Fenneteau, O., Maier-Redelsperger, M., Chomienne, C., Donadieu, J. Blood (2004) [Pubmed]
  3. Alpha1-antitrypsin and neutrophil elastase imbalance and lung cancer risk. Yang, P., Bamlet, W.R., Sun, Z., Ebbert, J.O., Aubry, M.C., Krowka, M.J., Taylor, W.R., Marks, R.S., Deschamps, C., Swensen, S.J., Wieben, E.D., Cunningham, J.M., Melton, L.J., de Andrade, M. Chest (2005) [Pubmed]
  4. Neutrophil elastase in respiratory epithelial lining fluid of individuals with cystic fibrosis induces interleukin-8 gene expression in a human bronchial epithelial cell line. Nakamura, H., Yoshimura, K., McElvaney, N.G., Crystal, R.G. J. Clin. Invest. (1992) [Pubmed]
  5. Protease-antiprotease imbalance in the lungs of children with cystic fibrosis. Birrer, P., McElvaney, N.G., Rüdeberg, A., Sommer, C.W., Liechti-Gallati, S., Kraemer, R., Hubbard, R., Crystal, R.G. Am. J. Respir. Crit. Care Med. (1994) [Pubmed]
  6. High molecular weight neurofilament proteins are physiological substrates of adduction by the lipid peroxidation product hydroxynonenal. Wataya, T., Nunomura, A., Smith, M.A., Siedlak, S.L., Harris, P.L., Shimohama, S., Szweda, L.I., Kaminski, M.A., Avila, J., Price, D.L., Cleveland, D.W., Sayre, L.M., Perry, G. J. Biol. Chem. (2002) [Pubmed]
  7. 4-hydroxy-2-nonenal pyrrole adducts in human neurodegenerative disease. Montine, K.S., Kim, P.J., Olson, S.J., Markesbery, W.R., Montine, T.J. J. Neuropathol. Exp. Neurol. (1997) [Pubmed]
  8. Polymorphonuclear (PMN) elastase levels in depressive disorders. Değer, O., Bekaroğlu, M., Orem, A., Orem, S., Uluutku, N., Soylu, C. Biol. Psychiatry (1996) [Pubmed]
  9. Efficacy and safety during long-term treatment of primary monosymptomatic nocturnal enuresis with desmopressin. Swedish Enuresis Trial Group. Tullus, K., Bergström, R., Fosdal, I., Winnergård, I., Hjälmås, K. Acta Paediatr. (1999) [Pubmed]
  10. Effects of antidepressant treatments on polymorphonuclear elastase levels in patients with depression. Bekaroğlu, M., Değer, O., Karahan, S.C., Bilici, M., Soylu, C., Orem, A. Journal of affective disorders. (2000) [Pubmed]
  11. Mutations associated with neutropenia in dogs and humans disrupt intracellular transport of neutrophil elastase. Benson, K.F., Li, F.Q., Person, R.E., Albani, D., Duan, Z., Wechsler, J., Meade-White, K., Williams, K., Acland, G.M., Niemeyer, G., Lothrop, C.D., Horwitz, M. Nat. Genet. (2003) [Pubmed]
  12. Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis. Horwitz, M., Benson, K.F., Person, R.E., Aprikyan, A.G., Dale, D.C. Nat. Genet. (1999) [Pubmed]
  13. A novel notch protein, N2N, targeted by neutrophil elastase and implicated in hereditary neutropenia. Duan, Z., Li, F.Q., Wechsler, J., Meade-White, K., Williams, K., Benson, K.F., Horwitz, M. Mol. Cell. Biol. (2004) [Pubmed]
  14. Antineutrophil cytoplasmic antibodies reacting with human neutrophil elastase as a diagnostic marker for cocaine-induced midline destructive lesions but not autoimmune vasculitis. Wiesner, O., Russell, K.A., Lee, A.S., Jenne, D.E., Trimarchi, M., Gregorini, G., Specks, U. Arthritis Rheum. (2004) [Pubmed]
  15. Elevated levels of matrix metalloproteinases in bronchoalveolar lavage fluid of emphysematous patients. Finlay, G.A., Russell, K.J., McMahon, K.J., D'arcy, E.M., Masterson, J.B., FitzGerald, M.X., O'Connor, C.M. Thorax (1997) [Pubmed]
  16. Clinical and immunoregulatory effects of roxithromycin therapy for chronic respiratory tract infection. Nakamura, H., Fujishima, S., Inoue, T., Ohkubo, Y., Soejima, K., Waki, Y., Mori, M., Urano, T., Sakamaki, F., Tasaka, S., Ishizaka, A., Kanazawa, M., Yamaguchi, K. Eur. Respir. J. (1999) [Pubmed]
  17. A neutrophil elastase inhibitor, sivelestat, ameliorates lung injury after hemorrhagic shock in rats. Toda, Y., Takahashi, T., Maeshima, K., Shimizu, H., Inoue, K., Morimatsu, H., Omori, E., Takeuchi, M., Akagi, R., Morita, K. Int. J. Mol. Med. (2007) [Pubmed]
  18. Mutations in the ELA2 gene encoding neutrophil elastase are present in most patients with sporadic severe congenital neutropenia but only in some patients with the familial form of the disease. Ancliff, P.J., Gale, R.E., Liesner, R., Hann, I.M., Linch, D.C. Blood (2001) [Pubmed]
  19. Changes in chromatin organization at the neutrophil elastase locus associated with myeloid cell differentiation. Wong, E.T., Jenne, D.E., Zimmer, M., Porter, S.D., Gilks, C.B. Blood (1999) [Pubmed]
  20. Congenital and acquired neutropenia. Berliner, N., Horwitz, M., Loughran, T.P. Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program. (2004) [Pubmed]
  21. Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia. Dale, D.C., Person, R.E., Bolyard, A.A., Aprikyan, A.G., Bos, C., Bonilla, M.A., Boxer, L.A., Kannourakis, G., Zeidler, C., Welte, K., Benson, K.F., Horwitz, M. Blood (2000) [Pubmed]
  22. Elastase and cathepsin G of human monocytes. Quantification of cellular content, release in response to stimuli, and heterogeneity in elastase-mediated proteolytic activity. Campbell, E.J., Silverman, E.K., Campbell, M.A. J. Immunol. (1989) [Pubmed]
  23. Adenoviral gene delivery of elafin and secretory leukocyte protease inhibitor attenuates NF-kappa B-dependent inflammatory responses of human endothelial cells and macrophages to atherogenic stimuli. Henriksen, P.A., Hitt, M., Xing, Z., Wang, J., Haslett, C., Riemersma, R.A., Webb, D.J., Kotelevtsev, Y.V., Sallenave, J.M. J. Immunol. (2004) [Pubmed]
  24. Three human elastase-like genes coordinately expressed in the myelomonocyte lineage are organized as a single genetic locus on 19pter. Zimmer, M., Medcalf, R.L., Fink, T.M., Mattmann, C., Lichter, P., Jenne, D.E. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  25. Specific inhibition of thrombin-induced cell activation by the neutrophil proteinases elastase, cathepsin G, and proteinase 3: evidence for distinct cleavage sites within the aminoterminal domain of the thrombin receptor. Renesto, P., Si-Tahar, M., Moniatte, M., Balloy, V., Van Dorsselaer, A., Pidard, D., Chignard, M. Blood (1997) [Pubmed]
  26. Thrombospondin is a tight-binding competitive inhibitor of neutrophil elastase. Hogg, P.J., Owensby, D.A., Mosher, D.F., Misenheimer, T.M., Chesterman, C.N. J. Biol. Chem. (1993) [Pubmed]
  27. Neutrophil serine proteinases activate human nonepithelial cells to produce inflammatory cytokines through protease-activated receptor 2. Uehara, A., Muramoto, K., Takada, H., Sugawara, S. J. Immunol. (2003) [Pubmed]
  28. Human neutrophil elastase induces hypersecretion of mucin from well-differentiated human bronchial epithelial cells in vitro via a protein kinase C{delta}-mediated mechanism. Park, J.A., He, F., Martin, L.D., Li, Y., Chorley, B.N., Adler, K.B. Am. J. Pathol. (2005) [Pubmed]
  29. Modulation of elastase binding to elastin by human alveolar macrophage-derived lipids. Fujita, J., Sköld, C.M., Daughton, D.M., Ertl, R.F., Takahara, J., Rennard, S.I. Am. J. Respir. Crit. Care Med. (1999) [Pubmed]
  30. Therapeutic level of functional human alpha 1 antitrypsin (hAAT) secreted from murine muscle transduced by adeno-associated virus (rAAV1) vector. Lu, Y., Choi, Y.K., Campbell-Thompson, M., Li, C., Tang, Q., Crawford, J.M., Flotte, T.R., Song, S. The journal of gene medicine. (2006) [Pubmed]
  31. Neutrophil elastase stimulates MUC1 gene expression through increased Sp1 binding to the MUC1 promoter. Kuwahara, I., Lillehoj, E.P., Hisatsune, A., Lu, W., Isohama, Y., Miyata, T., Kim, K.C. Am. J. Physiol. Lung Cell Mol. Physiol. (2005) [Pubmed]
  32. Electrospray ionization mass spectrometry as a mechanistic tool: mass of human leucocyte elastase and a beta-lactam-derived E-I complex. Knight, W.B., Swiderek, K.M., Sakuma, T., Calaycay, J., Shively, J.E., Lee, T.D., Covey, T.R., Shushan, B., Green, B.G., Chabin, R. Biochemistry (1993) [Pubmed]
  33. Susceptibility of baboon aorta elastin to proteolysis. Desfontaines, L., Hornebeck, W., Wei, S.M., Robert, L., Lafuma, C. Biol. Chem. Hoppe-Seyler (1990) [Pubmed]
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  36. Thromsbospondin-1 binds to the heavy chain of elastase activated coagulation factor V (FVaHNE) and enhances thrombin generation on the surface of a promyelocytic cell line. Isordia-Salas, I., Manns, J.M., Sainz, I., Parekh, H., DeLa Cadena, R.A. Thromb. Res. (2005) [Pubmed]
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  38. Neutrophil elastase induces MUC5AC mucin production in human airway epithelial cells via a cascade involving protein kinase C, reactive oxygen species, and TNF-alpha-converting enzyme. Shao, M.X., Nadel, J.A. J. Immunol. (2005) [Pubmed]
  39. Neutrophil elastase-initiated EGFR/MEK/ERK signaling counteracts stabilizing effect of autocrine TGF-beta on tropoelastin mRNA in lung fibroblasts. DiCamillo, S.J., Yang, S., Panchenko, M.V., Toselli, P.A., Naggar, E.F., Rich, C.B., Stone, P.J., Nugent, M.A., Panchenko, M.P. Am. J. Physiol. Lung Cell Mol. Physiol. (2006) [Pubmed]
  40. Utilization of the 1,2,5-thiadiazolidin-3-one 1,1 dioxide scaffold in the design of potent inhibitors of serine proteases: SAR studies using carboxylates. Kuang, R., Epp, J.B., Ruan, S., Chong, L.S., Venkataraman, R., Tu, J., He, S., Truong, T.M., Groutas, W.C. Bioorg. Med. Chem. (2000) [Pubmed]
  41. Interleukin-8 up-regulation by neutrophil elastase is mediated by MyD88/IRAK/TRAF-6 in human bronchial epithelium. Walsh, D.E., Greene, C.M., Carroll, T.P., Taggart, C.C., Gallagher, P.M., O'Neill, S.J., McElvaney, N.G. J. Biol. Chem. (2001) [Pubmed]
  42. Proteolysis of monocyte CD14 by human leukocyte elastase inhibits lipopolysaccharide-mediated cell activation. Le-Barillec, K., Si-Tahar, M., Balloy, V., Chignard, M. J. Clin. Invest. (1999) [Pubmed]
  43. Converting enzyme-independent release of tumor necrosis factor alpha and IL-1beta from a stimulated human monocytic cell line in the presence of activated neutrophils or purified proteinase 3. Coeshott, C., Ohnemus, C., Pilyavskaya, A., Ross, S., Wieczorek, M., Kroona, H., Leimer, A.H., Cheronis, J. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  44. Neutrophil elastase enzymatically antagonizes the in vitro action of G-CSF: implications for the regulation of granulopoiesis. El Ouriaghli, F., Fujiwara, H., Melenhorst, J.J., Sconocchia, G., Hensel, N., Barrett, A.J. Blood (2003) [Pubmed]
  45. Novel effects of neutrophil-derived proteinase 3 and elastase on the vascular endothelium involve in vivo cleavage of NF-kappaB and proapoptotic changes in JNK, ERK, and p38 MAPK signaling pathways. Preston, G.A., Zarella, C.S., Pendergraft, W.F., Rudolph, E.H., Yang, J.J., Sekura, S.B., Jennette, J.C., Falk, R.J. J. Am. Soc. Nephrol. (2002) [Pubmed]
 
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