Isolation of alpha 1-protease inhibitor from human normal and malignant ovarian tissue.

Bagdasarian, Andranik; Wheeler, Jean S.; Stewart, Gwendolyn J.; Ahmed, S. S.; Colman, Robert W.

doi:10.1172/jci110025

Cited by 13 publications

(4 citation statements)

References 42 publications

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“…[33][34][35] Based on the observations that IL-32 is activated by PR3 9 and AAT inhibits PR3, 36,37 we determined the impact of AAT on the expression of IL-32 (and other proinflammatory cytokines) and alloactivation. AAT, a member of the serine protease inhibitor family, is one of the major cytoprotective proteins in the circulation.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of IL-32 activation by α-1 antitrypsin suppresses alloreactivity and increases survival in an allogeneic murine marrow transplantation model

Marcondes

Tabellini

et al. 2011

Blood

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Interleukin (IL)-32 was originally identified in natural killer cells and IL-2-activated human T lymphocytes. As T cells are activated in allogeneic transplantation, we determined the role of IL-32 in human mixed lymphocyte cultures (MLCs) and GVHD. In allogeneic MLCs, IL-32 increased two-fold in responding T cells, accompanied by five-fold increases of TNF␣, IL-6, and IL-8. After allogeneic hematopoietic cell transplantation, IL-32 mRNA levels in blood leukocytes were statistically significantly higher in patients with acute GVHD (n ‫؍‬ 10) than in serial samples from patients who did not develop acute GVHD (n ‫؍‬ 5; P ‫؍‬ .02). No significant changes in IL-32 levels were present in patients with treated (n ‫؍‬ 14) or untreated (n ‫؍‬ 8) chronic GVHD, compared with healthy controls (n ‫؍‬ 8; P ‫؍‬ .5, and P ‫؍‬ .74, respectively). As IL-32 is activated by proteinase-3 (PR3), we determined the effect of the serine protease inhibitor ␣-1 antitrypsin (AAT) on IL-32 levels and showed suppression of IL-32 and T-lymphocyte proliferation in MLCs. In an MHC-minor antigen disparate murine transplant model, preconditioning and postconditioning treatment with AAT resulted in attenuation or prevention of GVHD and superior survival compared with albumin-treated controls (80% vs 44%; P ‫؍‬ .04). These findings suggest that AAT modulates immune and inflammatory functions and may represent a novel approach to prevent or treat GVHD. (Blood. 2011;118(18):5031-5039) IntroductionAn extensive literature describes the role of proinflammatory cytokines in the manifestations of conditioning-related toxicity in patients undergoing hematopoietic cell transplantation (HCT) and the immunologic interactions of donor and recipient cells that follow HCT. We were interested in determining specifically the involvement of IL-32 in the "cytokine storm" that has been described in the peri-HCT and post-HCT period. 1 For one, we and others have shown that tumor necrosis factor ␣ (TNF), which is consistently up-regulated in transplant recipients, is a potent inducer of IL-32. 2 Conversely, IL-32 has been shown to induce TNF, 2-5 suggesting the possibility of an amplification loop between these two cytokines. Secondly, IL-32 was originally identified in IL-2-activated T lymphocytes and natural killer (NK) cells, 6 supporting a potential role in T-cell activation and function after allogeneic HCT. Furthermore, IL-32 is present in supernatants of IL-12, IL-18, and IL-12 plus IL-18-stimulated human NK cells and in 7 the supernatant of concanavalin A-stimulated human PBMCs. 7 In addition, in patients with myelodysplastic syndrome who exhibit excessive apoptosis in hematopoietic cells, we reported, in agreement with others, that silencing of endogenous IL-32 significantly reduced apoptosis and the expression of other proinflammatory mediators. 3,8 Based on these data, we postulated a role for IL-32 in alloactivation and in GVHD. As IL-32 is activated via partial cleavage by proteinase-3 (PR3), 9 we hypothesized that the naturally occurring serine protease...

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Section: Discussionmentioning

confidence: 99%

Inhibition of IL-32 activation by α-1 antitrypsin suppresses alloreactivity and increases survival in an allogeneic murine marrow transplantation model

Marcondes

Tabellini

et al. 2011

Blood

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“…Protease inhibitors are believed to play a role by preventing the digestion of this tissue after the ovulation process. More specifically, SERPINE1 (plasminogen activator inhibitor-1) and SERPINA1 have previously been found in normal ovarian stroma and may contribute to the control of the ovulatory proteolytic activity [55,56]. We then narrowed our analysis to only serous TOV samples to check its associations to clinical parameters.…”

Section: Discussionmentioning

confidence: 99%

Protease inhibitor SERPINA1 expression in epithelial ovarian cancer

Normandin

Péant

Page

et al. 2010

Clin Exp Metastasis

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Epithelial ovarian cancer is the most lethal gynecologic cancer with a 5 years survival rate of 30-40% in patients diagnosed with high-grade invasive disease (TOV). This is in stark contrast to the 95% 5 years survival rate in ovarian cancer patients diagnosed with low malignant potential (LMP) disease. The progression from localized tumor to invasive metastasis involves matrix proteolysis. Protease inhibitors are thought to play a key role by limiting this process. Using the Affymetrix HG-U133A GeneChip array, we have studied all serine protease inhibitors and found several serpin family members that are differentially expressed between LMP and TOV serous tumors. SERPINA1 was selected for further study due to its high expression in the majority of LMP tumors and its low expression in TOV tumors; observations that were also validated by quantitative-PCR (Q-PCR). To study the effects of its over expression on different tumorigenic parameters, SERPINA1 was cloned in the pcDNA3.1+ plasmid which was subsequently used to derive stable clones from two invasive ovarian cancer cell lines, TOV-112D and TOV-1946. We found no effect of SERPINA1 over expression on tumor growth in SCID mice although cell migration and invasion were affected in in vitro assays. There was also no association between patient survival and SERPINA1 immunostaining, however, SERPINA1 localization was different in LMP (nuclear) and TOV (cytoplasmic) tumors. SERPINA1 remains an interesting candidate since protein homeostasis, regulated by proteases and their inhibitors, should be studied holistically in order to assess their full impact in tumor progression.

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“…This increased protease activity probably accounts for the mucification and dispersal of the cumulus cells, a character of mature oocytes. Ovarian autodigestion under these conditions is prevented by ovarian stromal cell production of a,antiprotease (Bagdasarian et al 1981).…”

Section: Discussionmentioning

confidence: 99%

Follicular fluid α₁‐antitrypsin—correlation with fertilizing capacity of oocytes

Imoedemhe

Shaw

1986

BJOG

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Follicular fluid and serum concentrations of a-antitrypsin (a,-AT) were determined by radial immunodiffusion in 72 samples obtained from 33 infertile women undergoing in-vitro fertilization and embryo transfer. A statistically significantly lower concentration of a,-AT was found in follicular fluids from which mature oocytes were recovered (mean 1-52, SE 0.06 g/l) than in those yielding immature oocytes (mean 2.96, SE 0.22 g/l). There was also a significantly higher rate of fertilization (85%) for oocytes from follicular fluids with &,-AT concentrations of S2.0 g/l than for those obtained when the a,-AT concentration was >2.0 g/l (only 25%). The mean follicular fluid a,-AT concentration (1 -52, SE 0.06 g/l) of follicles yielding mature oocytes was significantly lower than the relevant mean serum concentration (3.17, SE 0.10 g/l). There was, however, no significant difference between follicular and serum concentration of a,-AT in the group yielding immature oocytes or in the serum concentrations between the different oocyte maturity groups. The measurement of follicular ar,-AT may be a useful adjunct in predicting which oocytes are mature and likely to be fertilized.

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Isolation of alpha 1-protease inhibitor from human normal and malignant ovarian tissue.

Abstract: A B S T R A C T Proteolytic enzymes

Cited by 13 publications

References 42 publications

Inhibition of IL-32 activation by α-1 antitrypsin suppresses alloreactivity and increases survival in an allogeneic murine marrow transplantation model

Inhibition of IL-32 activation by α-1 antitrypsin suppresses alloreactivity and increases survival in an allogeneic murine marrow transplantation model

Protease inhibitor SERPINA1 expression in epithelial ovarian cancer

Follicular fluid α₁‐antitrypsin—correlation with fertilizing capacity of oocytes

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Isolation of alpha 1-protease inhibitor from human normal and malignant ovarian tissue.

Abstract: A B S T R A C T Proteolytic enzymes

Cited by 13 publications

References 42 publications

Inhibition of IL-32 activation by α-1 antitrypsin suppresses alloreactivity and increases survival in an allogeneic murine marrow transplantation model

Inhibition of IL-32 activation by α-1 antitrypsin suppresses alloreactivity and increases survival in an allogeneic murine marrow transplantation model

Protease inhibitor SERPINA1 expression in epithelial ovarian cancer

Follicular fluid α1‐antitrypsin—correlation with fertilizing capacity of oocytes

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Product

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Follicular fluid α₁‐antitrypsin—correlation with fertilizing capacity of oocytes