Disease relevance of SERPINB1

• In addition, treatment of myeloid cells with lipopolysaccharide, a complex glycolipid of gram-negative bacteria, activated NF-kappaB to bind the -821 element, together suggesting that enhancement of expression of the anti-inflammatory MNEI gene is linked to innate immune responses to bacterial infection [1].
• Effect of a synthetic leukocyte elastase inhibitor on thrombin-induced pulmonary edema in the rat [2].
• Aerosol treatment with MNEI suppresses bacterial proliferation in a model of chronic Pseudomonas aeruginosa lung infection [3].
• Decreased specific anti-elastase activity in the uninvolved skin of patients with psoriasis [4].
• As residual tumor size and performance status were common to both indices, the predictive power of this 2-covariate PI (PI2) was also assessed in the Danish study and, subsequently, validated in the Dutch patients [5].

Psychiatry related information on SERPINB1

• The LEI group showed significantly slower one- and two-finger reaction time, had an impaired ability to balance, and were compromised in their ability to maintain body temperature, when compared with the HEI group [6].

High impact information on SERPINB1

• Specific therapy for this disorder is available in the form of weekly intravenous infusions of human plasma alpha 1AT, which effectively reconstitute the anti-elastase screen of the lung in these individuals [7].
• Constitutive and inducible expression of SKALP/elafin provides anti-elastase defense in human epithelia [8].
• Circulating anti-elastase in systemic lupus erythematosus [9].
• cDNA encoding human monocyte/neutrophil elastase inhibitor (EI), a M(r) approximately 42,000 protein with serpin-like functional properties, has been sequenced [10].
• EI has greatest homology (50.1% identity of amino acids) with plasminogen activator inhibitor 2, also a monocyte protein, and ovalbumin and gene Y, which were previously grouped as an ancient branch of the serpin superfamily [10].

Chemical compound and disease context of SERPINB1

• HP1 and MNEI levels inversely correlate in a number of normal and leukemia myeloid cells and show strikingly opposite coordinated changes during differentiation of U937 cell line induced by retinoic acid [11].
• These data indicate that alanyl alanyl prolyl alanine chloromethylketone in the doses administered (1) had significant anti-elastase activity in vivo; (2) markedly decreased the extent of elastase-induced emphysema; and (3) produced no adverse toxic effect during the period covered by this study protocol [12].

Biological context of SERPINB1

• Increased levels of a related inhibitor Serpinb1 (monocyte/neutrophil elastase inhibitor) in the tissues of targeted mice suggests that compensation by other serpins reduces the impact of SPI3 deficiency in these animals and may explain the lack of a more obvious phenotype [13].
• The hydrolysis of peptide substrates reflects the specificity of the parent serpin including those from alpha-1-protease inhibitor and monocyte neutrophil elastase inhibitor, two potent inhibitors of elastase and Pr3 [14].
• By amplifying DNA of a somatic cell hybrid panel, ELANH2 was unambiguously localized to chromosome 6 [15].
• The molecular structure will help clarify the likely role of EI in regulating protease action and preventing tissue damage by phagocytic cells [10].
• This study demonstrates that MNEI has two functional reactive sites corresponding to the predicted P(1) and P(2) positions of the reactive center loop [16].

Anatomical context of SERPINB1

• Secretory leukocyte proteinase inhibitor is a major leukocyte elastase inhibitor in human neutrophils [17].
• Leukocyte elastase inhibitor (LEI) is a cytosolic component of lung macrophages and blood leukocytes that inhibits neutrophil elastase [18].
• On transient transfection, promoter activity of MNEI-luciferase constructs was highest in U937 myeloid cells, followed by K562 hematopoietic cells, followed by HeLa cervical carcinoma cells, indicating that the MNEI promoter is most active in myeloid cells and is also active in non-myeloid cells [1].
• MNEI is predominantly expressed in early haemopoietic progenitors while antitrypsin is mainly expressed in more mature myeloid precursors, peripheral blood granulocytes and mononuclear cells [19].
• Studies in sheep further demonstrated that the aerosolized pAAT and rAAT were each able to pass through alveolar epithelium and gain access to the interstitial compartment of the lung, thus increasing anti-elastase defenses of the lung interstitium [20].

Associations of SERPINB1 with chemical compounds

• Sequence alignment indicates that the reactive center P1 residue is Cys-344, consistent with abrogation of elastase inhibitory activity by iodoacetamide and making EI a naturally occurring Cys-serpin [10].
• The serpin MNEI inhibits elastase-like and chymotrypsin-like serine proteases through efficient reactions at two active sites [16].
• One was methionine 358, whose oxidation was known to cause loss of anti-elastase activity [21].
• Thus, heparin increases both the rate of inhibition by promoting the formation of a high affinity EI* intermediate and the rate of EI dissociation [22].
• Using synthetic peptides corresponding to full-length elafin (H2N-1AVT.....95Q-OH), the NH2-terminal domain (H2N-1AVT.....50K-OH) and the COOH-terminal domain (H2N-51PGS.....95Q-OH), we demonstrate that elafin's anti-elastase activity resides exclusively in the COOH-terminus [23].

Other interactions of SERPINB1

• Characterization and chromosomal localization of ELANH2, the gene encoding human monocyte/neutrophil elastase inhibitor [15].
• Here we show that MNEI has a broader specificity, efficiently inhibiting proteases with elastase- and chymotrypsin-like specificities [16].
• It had a comparable anti-elastase activity to that observed with a previously described IGF II-API fusion protein with the single mutation M351E [24].
• A specific leukocyte elastase inhibitor abrogated the increased detachment but catalase had no effect [25].
• Although the prototypic serine protease inhibitor phenyl methylsulfonylfluoride (PMSF) protected endothelium from PMNs, pure alpha-1-PI (also a potent anti-elastase) when added in physiologic amounts did not protect endothelial cells from PMN assault, suggesting that PMN oxidants might inactivate it [26].

Analytical, diagnostic and therapeutic context of SERPINB1

• Sequence analysis established that EI is a member of the serpin superfamily [10].
• Lung lavage fluid from patients with alpha 1-proteinase inhibitor deficiency or chronic obstructive bronchitis: anti-elastase function and cell profile [27].
• We hypothesized that recombinant MNEI would reduce inflammatory damage and enhance bacterial clearance from the lung in an animal model of chronic Pseudomonas aeruginosa infection [3].
• Administered MNEI was partially recovered in lavage fluid of treated rats as a 66-kDa complex with protease indicative of in vivo inhibition of elastase or a related protease [3].
• First, the surface of tumor infiltrating lymphocytes, TIL 660, the indicator cell line used for the purification of this mitogen, was shown to stain positively with an anti-elastase antibody using flow cytofluorometry for quantitation [28].

References