Disease relevance of TPSAB1

• As reported previously, during systemic anaphylaxis in patients without known mastocytosis, the ratio of B12- to G5-measured tryptase was always < 5 and approached unity (Schwartz L.B., T.R. Bradford, C. Rouse, A.-M. Irani, G. Rasp, J.K. Van der Zwan and P.-W.G. Van der Linden, J. Clin. Immunol. 14:190-204) [1].
• In this report, most mastocytosis patients with systemic disease have B12-measured tryptase levels that are elevated (> 20 ng/ml) and are at least 10-fold greater than the corresponding G5-measured tryptase level [1].
• Our findings suggest that the release of tryptase from activated mast cells may provide a signal for abnormal fibrosis in inflammatory disease [2].
• The alpha form of human tryptase is the predominant type present in blood at baseline in normal subjects and is elevated in those with systemic mastocytosis [1].
• Expression of mast cell tryptase by myeloblasts in a group of patients with acute myeloid leukemia [3].
• Angiogenesis, measured as microvessel density, was highly correlated with MC tryptase-positive cell count in pterygium tissues [4].

Psychiatry related information on TPSAB1

• Comparisons were made with: (1) symptom scores; (2) olfaction changes; and (3) nasal secretion levels of histamine, tryptase, leukotriene C4, serum albumin (a marker of vascular permeability), lactoferrin (a marker of local glandular secretion), and inflammatory cells in nasal scrapings [5].
• However, after a latency period of a few months, tryptase concentrations declined and then reached a plateau [6].

High impact information on TPSAB1

• Tryptase levels as an indicator of mast-cell activation in systemic anaphylaxis and mastocytosis [7].
• Tryptase, a neutral protease selectively concentrated in the secretory granules of human mast cells (but not basophils), is released by mast cells together with histamine and serves as a marker of mast-cell activation [7].
• In 17 patients with systemic mastocytosis, concentrations of tryptase in plasma were linearly related to those of histamine (P less than 0.01) [7].
• One patient had a myocardial infarction after anaphylaxis in response to a wasp sting and an elevated tryptase level of 25 ng per milliliter [7].
• In contrast, serum tryptase levels were less than 5 ng per milliliter in all patients presenting with myocardial disease (n = 8, 6 with hypotension) or sepsis (n = 6, 3 with hypotension) and in the controls (n = 20) [7].

Chemical compound and disease context of TPSAB1

• BACKGROUND: Human beta-tryptase is a mast cell specific trypsin-like serine protease that is thought to play a key role in the pathogenesis of diverse allergic and inflammatory disorders like asthma and psoriasis [8].
• The increases of C3 and CCL2 synthesis by C3a and C3 activation by skin mast cell tryptase delineates a novel amplification loop of complement activation and inflammatory responses that may influence the pathogenesis of allergic/inflammatory skin diseases [9].
• Luminal trypsin and tryptase are elevated in the colon of inflammatory bowel disease patients [10].
• Tryptase-induced DNA synthesis was inhibited by preincubation of the cells with pertussis toxin, calphostin C, or genistein [11].
• Pretreatment of cells with metabolic inhibitors or pertussis toxin reduced the ability of mast cells to release tryptase or histamine [12].

Biological context of TPSAB1

• These results suggest that the proteases tryptase and chymase secreted from mast cells in skin may affect the behavior of surrounding cells by the hydrolysis of PARs expressed by these cells [13].
• We also compared the type, frequency and distribution of single nucleotide polymorphisms in TPS1 and TPS2 and we observed that the polymorphism frequency within these two loci is unexpectedly high (approximately 1 SNP every 90 bp) and that some of the allele frequencies differ significantly among the three ethnic groups [14].
• Identification of tryptase- and chymase-related gene clusters in human mast cells using microarrays [15].
• Both thrombin and tryptase have been shown to induce smooth muscle cell proliferation in vitro [16].
• These loops are located around the active site of beta-tryptase and differ considerably in length and conformation from loops of other trypsin-like proteinases [17].

Anatomical context of TPSAB1

• One mast-cell product, the serine protease tryptase, is known to activate protease-activated receptor 2 (PAR2) and cause proliferation of fibroblasts [18].
• Reaction of mast cell proteases tryptase and chymase with protease activated receptors (PARs) on keratinocytes and fibroblasts [13].
• The protease-activated receptor-2 (PAR-2) is present on human airway smooth muscle (ASM) cells and can be activated by mast cell tryptase, trypsin, or an activating peptide (AP) [19].
• However, little is known about the effects of mast cell-specific mediators, such as tryptase, on eosinophils [20].
• The specific inhibitors of thrombin, trypsin and tryptase inhibited the actions of these proteinases on T cells, indicating that the enzymatic activity is essential for their actions [21].

Associations of TPSAB1 with chemical compounds

• Heparin, a GAG that binds to tryptase, stabilizing its functional form, also inhibited tryptase-induced Ca2+ mobilization [13].
• Thrombin and tryptase responses were dose-dependently inhibited by leupeptin [16].
• The 3-A crystal structure of human beta-tryptase in a complex with 4-amidinophenyl pyruvic acid shows four quasi-equivalent monomers arranged in a square flat ring of pseudo 222 symmetry [17].
• A second cDNA for human tryptase, called beta-tryptase, was cloned from a mast cell cDNA library in lambda ZAP [22].
• Asp244, which is substituted for the Gly found in dog tryptase and in most serine proteases, is present in the putative substrate binding pocket and may confer additional substrate specificity on human tryptase for basic residues [23].

Physical interactions of TPSAB1

• We also show that the majority of the TAME-esterase activity detected in nasal secretions during the allergic response is due to activities consistent with a plasma kallikrein/alpha 2-macroglobulin complex and with mast cell tryptase [24].
• These findings suggest that tryptase TL2 is important in target site recognition and binding of HIV-1 in co-operation with CD4 receptor in the initial process of HIV-1 infection [25].
• In the latter case, studies in Chinese hamster lung fibroblasts using specific receptor agonists and antagonists or receptor-transfected cell lines reveal a requirement for the activation of a G protein (Gi) negatively coupled to adenylate cyclase to act synergistically with tryptase [26].

Enzymatic interactions of TPSAB1

• These findings suggest that mast cell beta-tryptase selectively cleaves ASM-derived eotaxin and RANTES and abrogates their chemotactic activities, thus providing an explanation for the eosinophil paucity in asthmatic ASM bundles [27].
• Tryptase also cleaved the analogous thrombin receptor peptide at the activating site but less efficiently [28].
• Tryptase hydrolyzes VIP rapidly at several sites (Arg12, Arg14, Lys20, and Lys21) with an overall kcat/Km of 1.5 x 10(5) M-1 s-1 and hydrolyzes PHM primarily at a single site (Lys20) with a kcat/Km of 1.9 x 10(4) M-1 s-1 [29].
• Tryptase from human mast cells has been shown (in vitro) to catalyze the destruction of fibrinogen and high-molecular-weight kininogen as well as the activation of C3a and collagenase [30].

Regulatory relationships of TPSAB1

• Thus, the tryptase epsilon gene is expressed in the airways in a developmentally regulated manner that is different from that of other human tryptase genes [31].
• Tryptase inhibits motility of human spermatozoa mainly by activation of the mitogen-activated protein kinase pathway [32].
• However, the tryptase induced endothelial cells to express large amounts of IL-8 continually over a 40-h period [33].
• Tryptase is a mitogen for epithelial cells and stimulates IL-8 production and ICAM-1 expression by these cells [34].
• PARs-1, -3 and -4 are activated by thrombin, while PAR-2 is activated by trypsin or mast cell tryptase, but not by thrombin [35].

Other interactions of TPSAB1

• We studied the effect of beta-tryptase on the immunoreactivities of human ASM cell-derived and recombinant eotaxin and other recombinant chemokines that are known to be produced by human ASM cells [27].
• RESULTS: High percentages (>70%) of tryptase-positive cells showing CCR3 expression were found in the skin and in the intestinal submucosa, whereas much lower percentages (< or = 20%) were found in the intestinal mucosa and in the lung interstitium [36].
• Tryptase (TPSB2) was expressed at the highest level among all transcripts and its expression level reached a plateau at 8 weeks [15].
• RESULTS: Tryptase induced the release of eosinophil peroxidase and beta-hexosaminidase from peripheral blood eosinophils but had no effect on RANTES release [20].
• We demonstrate that tryptase can activate peripheral mononuclear cells (PBMCs), isolated from healthy donors as well as MS patients for the release of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6 and IL-1beta [37].

Analytical, diagnostic and therapeutic context of TPSAB1

• Tryptase and chymase are the two major granular proteases present in human mast cell (MC)s. We used oligonucleotide microarray to measure the levels of approximately 22,000 transcripts in cord blood-derived MCs at 4 weeks, 8 weeks, 12 weeks and 18 weeks in culture [15].
• Localization of both alpha- and beta-tryptase sequences to human chromosome 16 was then performed by analysis of DNA preparations from 25 human/hamster somatic hybrids by PCR [22].
• Tryptase was isolated from human lung tissue by ion-exchange and affinity chromatography [2].
• In this study, serum total tryptase levels were determined in 150 patients with acute leukemias (de novo acute myeloid leukemia [AML], n = 108; secondary AML, n = 25; acute lymphoid leukemia [ALL], n = 17) by fluoroenzyme immunoassay [3].
• Immunohistochemical staining of bone marrow sections with anti-tryptase antibody as well as immunoelectron microscopy revealed tryptase expression in the cytoplasm of myeloblasts [3].

References