Generation of soluble P‐ and E‐selectins in vivo is dependent on expression of P‐selectin glycoprotein ligand‐1

Abstract

of soluble P-and E-selectins in vivo is dependent on expression of P-selectin glycoprotein ligand-1. J Thromb Haemost 2007; 5: 599-603.Summary. Background: Factors contributing to the generation of soluble P-and E-selectins remain unclear. Results: This work demonstrates that mice lacking P-selectin glycoprotein ligand-1 (Psgl-1) are deficient in soluble P-selectin (sP-sel), which is due to a defective binding interaction between PSGL-1 and P-sel, because mice lacking a(1,3)-fucosyltransferase-VII are also deficient in sP-sel. Psgl-1 )/) mice are also deficient in soluble E-selectin (sE-sel) indicating that leukocyte interactions with endothelial cells lead to the generation of sE-sel. The generation of sE-sel requires an interaction between PSGL-1 and P-sel, as deficiency of sE-sel is observed in both Psgl-1and P-sel )/) mice. Bone marrow transplantation from Psgl-1 )/)to Psgl-1 +/+ mice leads to deficiency of sP-sel and sE-sel in recipient mice, establishing the importance of bone marrowderived PSGL-1 toward the generation of sP-sel and sE-sel. Bone marrow transplantation from P-sel )/) to P-sel1 +/+ mice does not lead to a significant reduction in sP-sel, confirming the importance of the endothelium toward the liberation of sP-sel. Conclusion: sP-sel and sE-sel reflect an interaction between leukocyte PSGL-1 and endothelial P-sel.

P-selectin glycoprotein ligand-1 deficiency leads to cytokine resistance and protection against atherosclerosis in apolipoprotein E deficient mice

“…We have previously demonstrated in lean and obese mice that hematopoietic Psgl-1 deficiency leads to reduced generation of sP-sel, sE-sel, and Mcp-1 12,14 . This unexpected regulatory role of hematopoietic Psgl-1 deficiency appears to involve transcriptional repression of endothelial adhesive and chemotactic factors 12 .…”

Targeting selectins and selectin ligands in inflammation and cancer

“…Soluble forms of E-selectin have been detected in supernatants of cytokine-activated endothelial cells [125] and are elevated in serum of subjects with bronchial asthma [126,127], eczema [128], psoriasis [129][130][131], atopic and allergic dermatitis [131][132][133][134][135], Kawasaki disease [136], Guillain-Barre syndrome [137] or Graves disease [138] compared with normal subjects. Soluble E-selectin is deficient in mice null for PSGL-1, suggesting a role for PSGL-1 in solubilization [139]. It may be that soluble E-selectin exacerbates symptoms in inflammatory disease through activation of β2 integrins, modulation of leukocyte movement and/or augmentation in release of reactive oxygen species through stimulation of the respiratory burst [140].…”

P-Selectin Glycoprotein Ligand-1 Regulates Adhesive Properties of the Endothelium and Leukocyte Trafficking Into Adipose Tissue

“…Since sP-sel levels are positively regulated by leukocyte Psgl-1 in the basal state 18, we determined if sP- and sE-sel levels in both genetic and diet-induced obesity were also reduced in the setting of Psgl-1 deficiency. In this study, sP-sel and sE-sel were lower in Lepr db/db ,Psgl-1 −/− mice and Psgl-1 −/− mice on a high-fat, high-sucrose diet compared to Lepr db/db ,Psgl-1 +/+ mice and Psgl-1 +/+ mice on a high-fat, high-sucrose diet, respectively.…”

“…The reduced circulating levels of these proteins were associated with corresponding reduced gene transcription in lung and perigonadal adipose tissue. The cell source of the transcriptional differences were attributed to the endothelial cells within lung and perigonadal adipose tissue because the factors measured were either exclusively or primarily expressed by the endothelium 18, 20-23. Lung tissue was used for transcriptional studies because it is a rich source of endothelial cells, and inflammation in the lung is regulated by IL-1β 24.…”