Disease relevance of PPBP

• Five of these nine patients with anti-IL-8 or anti-NAP-2 developed thrombosis during heparin treatment, which is not statistically different from the patients with H-PF4 antibodies [1].
• Antibodies to IL-8 and NAP-2 were not observed in control patients (n = 38), patients with HAT and H-PF4 autoantibodies (n = 72), patients with autoimmune diseases (n = 21), or patients with non-HAT thrombocytopenia (n = 30) [1].
• The human melanoma growth-stimulatory activities (MGSA alpha, beta, gamma/GRO) are products of immediate early genes coding for cytokines that exhibit sequence similarity to platelet factor-4 and beta-thromboglobulin [2].
• Beta thromboglobulin and platelet factor 4 in bronchoalveolar lavage fluid of patients with systemic sclerosis [3].
• A neutrophil-activating peptide, NAP-2, was found to be produced in cultures of human mononuclear cells in the presence of E. coli lipopolysaccharide or phytohaemagglutinin [4].

Psychiatry related information on PPBP

• There were significant increases in the plasma concentrations of the platelet-secreted proteins platelet factor 4 and beta-thromboglobulin and epinephrine and norepinephrine immediately before speaking, which demonstrates that platelet activation and secretion occur in association with this type of emotional stress [5].
• Decreased brain-derived neurotrophic factor (BDNF)- and beta-thromboglobulin (beta-TG)- blood levels in Alzheimer's disease [6].
• The variations of FVII, PAI-1, TAT complexes, fibrinopeptide A, D-Dimers and beta thromboglobulin plasma levels were studied on 30 sedentary men, smokers and non-smokers, who were admitted to a 6 months' program of physical training and smoking cessation [7].
• RESULTS: Psychotic symptoms (hallucinations) were observed in three (0.8%) of 356 TGB-treated patients and none of 198 placebo-treated patients (p = 0.556, NS) [8].
• Beta thromboglobulin and alcohol consumption [9].

High impact information on PPBP

• Pc3/Tis21 has a strong sequence similarity to the human antiproliferative BTG1 gene cloned from a chromosomal translocation of a B-cell chronic lymphocytic leukaemia [10].
• The platelet counts declined while the plasma concentration of beta-thromboglobulin and the ratio of beta-thromboglobulin to platelet factor 4 increased, indicating in vivo activation of platelets [11].
• Nucleotide sequence and in vitro translation results indicate that 9E3 mRNA encodes an 11 kd polypeptide that is homologous to human connective tissue activating peptide III (CTAP-III), a mitogenic platelet alpha-granule protein, and to beta-thromboglobulin and platelet factor 4 [12].
• A significant part of macrophage-derived growth factor consists of at least two forms of PDGF [13].
• One of the secretory products of activated macrophages is MDGF, a growth factor (or factors) for fibroblasts, 3T3 cells, smooth muscle, and vascular endothelium [13].

Chemical compound and disease context of PPBP

• The mean values of the plasma BTG, PF4, and 5-HT concentrations in the migraine group and the MCH group were significantly higher than those in healthy controls [14].
• The mean levels of LA-PF4/beta TG antigen excreted in urine of six normal individuals and 10 patients with chronic renal failure were 57.75 and 1461.5 ng/100 mg of creatinine per day, respectively [15].
• The plasma levels of beta-Thromboglobulin (beta-TG) and Platelet Factor 4 (PF4) were measured in patients during the normal obstetrical period and in pre-eclampsia [16].
• Beta-thromboglobulin and platelet factor 4 in polycythemia patients treated by ticlopidine [17].
• We determined the levels of beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4) and the genotype distributions of PlA and a variable number tandem repeat (VNTR) polymorphism of GP 1b in subjects with acute stroke (n=609) and healthy control subjects (n=435) [18].

Biological context of PPBP

• Markers for association mapping were chosen after determining patterns of linkage disequilibrium across the surrounding region of chromosome 4q, a 550-kb segment containing nine genes, extending from AFP to PPBP [19].
• NAP-2-induced elastase release and a rise in cytosolic free Ca2+ at concentrations between 0.3 and 100 nM, and neutrophil chemotaxis at concentrations between 0.03 and 10 nM [20].
• Superoxide production, a measure of the respiratory burst, was obtained with increasing concentrations of IL-8 with maximum effects at 25 to 50 nM, but no response was observed upon challenge with GRO alpha or NAP-2 up to 1000 nM [21].
• Instead of inducing cell activation, continuous accumulation of the chemokine in the surroundings of the processing cells results in the down-regulation of specific surface-expressed NAP-2 binding sites and in the desensitization of chemokine-induced PMN degranulation [22].
• Further investigations of this type demonstrated that a chimeric PF4 protein (AELR/PF4) in which PF4's N-terminus was replaced with the first four amino acids of NAP-2 was also a potent inhibitor of megakaryocytopoiesis [23].

Anatomical context of PPBP

• It could be generated from PBP and/or CTAP-III released from activated platelets and lead to the accumulation of neutrophils in platelet aggregates [20].
• NAP-2 was generated whenever monocytes and platelet release supernatant were present [24].
• Monocytes alone did not yield NAP-2 and no neutrophil-activating peptide was generated by lymphocytes [24].
• The inhibitory effects of NAP-2 and MIP-1 alpha could not be overcome by adding physiologically relevant amounts of recombinant human megakaryocyte growth and development factor (MGDR) (50 ng/mL) to the cultures [23].
• Here we show for the first time that activated human skin mast cells (MCs) convert CTAP-III into biologically active NAP-2 through proteolytic cleavage by released chymase [25].

Associations of PPBP with chemical compounds

• The monocyte-conditioned medium was found to cleave purified CTAP-III into NAP-2 through proteinases that were highly sensitive to PMSF, moderately sensitive to leupeptin and insensitive to EDTA [24].
• Competitive radioimmunoassay demonstrated a low but significant immunologic cross-reactivity between human and porcine platelet factor 4, and between porcine platelet basic protein and a group of human secreted platelet proteins that bind to heparin with low affinity (beta-thromboglobulin [beta TG] and low affinity platelet factor 4) [26].
• 0. The amino acid composition of porcine platelet basic protein resembled that of human low affinity platelet factor 4 (LA-PF4), except that the porcine protein did not contain tyrosine [26].
• Because cleavage of the CTAP-III-unrelated substrate substance P was also affected by PF-4, our results suggest a regulatory role for PF-4 not only in NAP-2 generation but also in neutrophil- and MC-mediated processing of other physiologically relevant inflammatory mediators [25].
• The neutrophil-activating proteins interleukin 8 and beta-thromboglobulin: in vitro and in vivo comparison of NH2-terminally processed forms [27].

Physical interactions of PPBP

• IL-8 and NAP-2 differ in their capacities to bind and chemoattract 293 cells transfected with either IL-8 receptor type A or type B [28].
• Although two IL-8R types are expressed by PMN, only CXCR2 binds NAP-2 and IL-8 with equally high affinity [29].

Enzymatic interactions of PPBP

• From several PMN-derived proteases tested, only cathepsin G had the capacity to cleave CTAP-III into NAP-2 with high specificity and in a relatively short period of time (30 min) [30].

Regulatory relationships of PPBP

• Blocking monoclonal antibodies (MoAbs) specific for CXCR-2 or CXCR-1 either suppress the first optimum of NAP-2-induced chemotaxis or drastically reduce the second one, respectively [31].
• We have cloned the cDNA for PBP and expressed constructs coding for the CTAP-III and NAP-2 polypeptides in Escherichia coli [32].
• Pretreatment of HMVECs with beta-thromboglobulin enhanced monocyte arrest in the presence of cathepsin G generating NAP-2 [33].
• However, fractions rich in the most extensively processed forms of beta TG (e.g. NAP-2) as well as pure NAP-2 did induce lactoferrin release from granulocytes, whereas fractions containing only the longer forms (e.g. connective tissue-activating peptide III) were inactive [27].
• IL-8 and neutrophil-activating peptide-2 (NAP-2) are two closely related C-X-C chemokines that differ in their abilities to induce chemotaxis of human polymorphonuclear leukocytes (PMN) [29].

Other interactions of PPBP

• By contrast, only minimal if any effects were obtained with PBP, CTAP-III, and PF-4 up to 100 nM [20].
• NAP-3 (MGSA/gro) appears to represent the first member of the novel supergene family of beta-thromboglobulin-like host defense cytokines, which expresses both mitogenic as well as proinflammatory properties at the nanogram level [34].
• Unlabeled IL-8 fully inhibited this cross-linking and the binding of labeled GRO alpha or NAP-2 to the high-affinity sites on neutrophils or neutrophil membranes [35].
• Changes in [Ca2+]i were found after addition of RANTES, MIP-1 alpha, and NAP-2 (10 nmol/L) to unprimed eosinophils [36].
• Human IL-8 receptor A binds with low affinity to MGSA or NAP-2 [37].

Analytical, diagnostic and therapeutic context of PPBP

• It may be that antibodies to IL-8 and NAP-2 have weaker affinity for heparin and that the ELISA system may not reflect in vivo heparin-chemokine complex formation [1].
• Increased microvascular permeability in vivo in response to intradermal injection of neutrophil-activating protein (NAP-2) in rabbit skin [38].
• Receptor expression studies using flow cytometry indicated that in COPD, monocyte expression of CXCR2 is regulated differently from nonsmokers and smokers, which may account for the enhanced migration toward GROalpha and NAP-2 [39].
• METHODS: BTG and PF-4 were measured by enzyme immunoassay in BALF from 37 patients with systemic sclerosis [3].
• Beta-thromboglobulin (beta TG) and platelet factor 4 (PF4) have been localised in megakaryocytes and platelets using immunofluorescence and immunoperoxidase techniques [40].

References