Disease relevance of Selp

• Interaction of P-selectin and PSGL-1 generates microparticles that correct hemostasis in a mouse model of hemophilia A [1].
• Eosinophil adhesion to nasal polyp endothelium is P-selectin-dependent [2].
• Synergistic effects of L- and P-selectin in facilitating tumor metastasis can involve non-mucin ligands and implicate leukocytes as enhancers of metastasis [3].
• Here we show similar findings with a murine adenocarcinoma in syngeneic immunocompetent mice but involving a different P-selectin ligand, possibly a sulfated glycolipid [3].
• This is supported by the presence of hypercoagulability, increased CD61 and CD62P on resting platelets, and higher plasma soluble P-selectin in L(-/-)/A(-/-)/FG(-/-) mice as compared to L(-/-)/A(-/-), FG(-/-), or wild-type mice [4].
• P-selectin expression in the cerebrovasculature, which is also implicated in cerebral ischemia and reperfusion injury, was shown to be distal to and dependent on complement activation [5].

Psychiatry related information on Selp

• One of the most striking observations is the combined expression of mucosal addressin cell adhesion molecule-1 (MAdCAM-1) and P-selectin by maternal vessels of the vascular zone during the critical period of initial placenta development [6].

High impact information on Selp

• Selectins are a family of three cell adhesion molecules (L-, E-, and P-selectin) specialized in capturing leukocytes from the bloodstream to the blood vessel wall [7].
• The alpha(1,3)fucosyltransferase Fuc-TVII controls leukocyte trafficking through an essential role in L-, E-, and P-selectin ligand biosynthesis [8].
• We demonstrate here that mice deficient in alpha(1,3) fucosyltransferase Fuc-TVII exhibit a leukocyte adhesion deficiency characterized by absent leukocyte E- and P-selectin ligand activity and deficient HEV L-selectin ligand activity [8].
• Leukocyte rolling and extravasation are severely compromised in P selectin-deficient mice [9].
• P selectin, expressed on surfaces of activated endothelial cells and platelets, is an adhesion receptor for leukocytes [9].

Chemical compound and disease context of Selp

• To determine if P-selectin was expressed on the membrane of the nasal polyp endothelium we compared P-selectin expression in normal skin and nasal polyps after acetone fixation, which permeabilizes cells, and paraformaldehyde, which only allows staining of membrane expressed receptors [2].
• Moreover, although selectin blockade by heparin 6 to 18 hours after tumor cell injection was synergistic with P-selectin deficiency in reducing metastasis, there was no further effect in L-selectin-deficient animals [10].
• The inhibited edema and hemorrhage paralleled reduced infiltration of neutrophils and mast cells that expressed significant levels of P-selectin glycoprotein ligand-1 [11].
• Therefore, bleomycin-induced lung fibrosis was examined in E-selectin-/- mice, P-selectin-/- mice, and E-selectin-/- mice treated with anti-P-selectin monoclonal antibody (mAb) in comparison of wild-type mice [12].
• To determine the relative in vivo importance of endothelial expressed adhesion molecules to eosinophil rolling, adhesion, and transmigration, we have induced eosinophilic peritonitis using ragweed allergen in P-selectin-deficient, intracellular adhesion molecule-1 (ICAM-1)-deficient and control wild-type mice [13].

Biological context of Selp

• These kinetics are consistent with a model in which PSGL-1 is the predominant neutrophil P-selectin ligand but is not a required counterreceptor for E-selectin under in vivo physiological conditions [14].
• Stimulation of P-selectin transcription by IL-4 or OSM required new protein synthesis and tyrosine phosphorylation of cellular proteins [15].
• These results, coupled with the closely controlled genetics of this study, indicate that reductions in the expression of P-selectin, ICAM-1, or E-selectin provide direct protection from atherosclerotic lesion formation in this model [16].
• The fourth TNF-alpha-inducible cell adhesion mechanism was blocked by antibodies specific for mouse P-selectin [17].
• Constitutive P-selectin expression is largely absent in cultured murine brain microvascular EC (BMEC) monolayers, but interleukin-1beta and tumor necrosis factor-alpha stimulation for 4 hours leads to dramatic P-selectin upregulation [18].

Anatomical context of Selp

• In addition, the pregnant uteri of syngeneic Selp(-/-) x Selp(-/-) mice were investigated and compared to the controls [19].
• In the resistant mice, interleukin-15 mRNA in the gingiva and Selp mRNA in the spleen are present at higher levels [20].
• This role of activated platelets in atherosclerosis is attributed to platelet P-selectin-mediated delivery of platelet-derived proinflammatory factors to monocytes/leukocytes and the vessel wall [21].
• The increased expression of P-selectin may facilitate the emigration of leukocytes into sites of chronic or allergic inflammation [15].
• During acute inflammation, P-selectin is transiently mobilized from Weibel-Palade bodies to the surface of histamine-activated endothelial cells, where it mediates rolling adhesion of neutrophils under hydrodynamic flow [15].

Associations of Selp with chemical compounds

• P-selectin glycoprotein ligand-1-deficient mice have impaired leukocyte tethering to E-selectin under flow [22].
• Although heparin can block both P- and L-selectin in vitro, the in vivo effect of a single heparin dose given before tumor cells seems to be completely accounted for by blockade of P-selectin function [3].
• The best-characterized selectin ligand is P-selectin glycoprotein-1 (PSGL-1) that supports P-selectin- dependent rolling in vitro and in vivo [23].
• These results suggest that early migration occurs independent of the lymphocyte integrin VLA-4 and endothelial VCAM, but does require increased surface expression of endothelial P selectin [24].
• Tumor necrosis factor-alpha (TNF-alpha) or lipopolysaccharide (LPS) increases synthesis of P-selectin in murine but not in human endothelial cells [25].

Physical interactions of Selp

• These studies confirmed that core-2 O-glycans attached to Thr-57 play a critical role in supporting L- and P-selectin-dependent rolling and revealed that additional binding sites support >75% of E-selectin-mediated rolling [26].
• P-selectin glycoprotein ligand-1 (PSGL-1) binding to P-selectin controls early leukocyte rolling during inflammation [27].
• Treatment of WEHI-3B cells with trypsin or neuraminidase abolished their ability to interact with P-selectin [28].
• Both P-selectin expression and fibrinogen binding in response to CRP were also decreased to a similar extent in p85alpha-/- platelets [29].
• Treatment of HSA with OSGE significantly reduced binding of both P-selectin and I [30].

Enzymatic interactions of Selp

• Fuc-TVII deficiency also deletes expression of E- and P-selectin ligands by Th1 and T cytotoxic 1 (Tc1) lymphocytes, annuls T cell trafficking to inflamed cutaneous sites in vivo, and thereby controls an essential component of the efferent phase of the cutaneous immune response [31].

Co-localisations of Selp

• With confocal microscopy, we found that the typical rodlike shape of the Weibel--Palade body is missing in vWf -/- endothelial cells and that part of the P-selectin content in the vWf -/- cells colocalized with LAMP-1, a lysosomal marker [32].

Regulatory relationships of Selp

• Rolling in both wild-type and ICAM-1-deficient mice 60-120 min after trauma was significantly inhibited by a P-selectin monoclonal antibody (mAb) (RB40.34) [33].
• P-Selectin is constitutively expressed on the extracellular surface of macrophages but is only partially colocalized with PSGL-1 [34].
• Microspheres coated with combinations of L-selectin and sLe(x) interacted with surgically stimulated cremaster venules in a P-selectin-dependent manner [27].
• PMN adhesion was decreased significantly (p<0.001) after the incubation of resting EC or TNFalpha-activated EC-seeded prostheses with a blocking monoclonal antibody (LYP20) directed against the P-selectin [35].
• The P-selectin mRNA was transiently induced at early time points while up-regulation of the E-selectin mRNA was more prolonged [36].

Other interactions of Selp

• In contrast, an mAb (KAT-1) blocking ICAM-1 binding to leukocyte function-associated antigen 1 did not block residual rolling in P-selectin-deficient mice [33].
• Recently, our laboratory showed that platelets, like leukocytes, roll on activated endothelium expressing P-selectin, thus suggesting a role for P-selectin in hemostasis (Frenette et at, Proc Natl Acad Sci USA 92:7450, 1995) [37].
• Significant levels of eotaxin were detected in response to IL-13/IL-4 in both tissues in P-selectin-deficient animals [38].
• In conclusion, the regulatory role of P-selectin in leukocyte transmigration elicited by IL-13 appears to be tissue-specific, a phenomenon that is independent of the ability of the cytokine to stimulate eotaxin generation [38].
• MMP-9 blockade is associated with an attenuation of TNF-alpha release and endothelial CD62P expression, weakly protects from early microvascular/hepatocellular I/R damage, but improves postischemic survival [39].

Analytical, diagnostic and therapeutic context of Selp

• In addition immunofluorescence with confocal microscopy demonstrated lumenal staining of nasal polyp endothelium indicating that P-selectin was located on the surface of endothelial cells while in skin only an intracellular granular distribution was apparent [2].
• Here, we demonstrate that peritoneal macrophages isolated by peritoneal lavage of unchallenged mice express P-selectin on the plasma membrane [34].
• Providing +/+ platelets to P/E-/- mice by bone marrow transplantation did not rescue the immunodeficient phenotype, suggesting that platelet P-selectin does not have an active function in the recruitment of leukocytes into inflammatory sites [40].
• IL-13 caused dose- and time-dependent increases of P-selectin expression, as assessed by flow and laser scanning cytometry [41].
• In contrast, expression of meningeal and choroid plexus-associated P selectin was upregulated 2 h after adoptive transfer, but not at 48 h [24].

References