title: Differential regulation of human and murine P-selectin expression and function in vivo.
abstract: Leukocytes roll on P-selectin after its mobilization from secretory granules to the surfaces of platelets and endothelial cells. Tumor necrosis factor (TNF), IL-1β, and lipopolysaccharide increase synthesis of P-selectin in murine but not in human endothelial cells. To explore the physiological significance of this difference in gene regulation, we made transgenic mice bearing the human Selp gene and crossed them with mice lacking murine P-selectin (Selp(-/-)). The transgenic mice constitutively expressed human P-selectin in platelets, endothelial cells, and macrophages. P-selectin mediated comparable neutrophil migration into the inflamed peritoneum of transgenic and wild-type (WT) mice. Leukocytes rolled similarly on human or murine P-selectin on activated murine platelets and in venules of the cremaster muscle subjected to trauma. However, TNF increased murine P-selectin in venules, slowing rolling and increasing adhesion, whereas it decreased human P-selectin, accelerating rolling and decreasing adhesion. Both P- and E-selectin mediated basal rolling in the skin of WT mice, but E-selectin dominated rolling in transgenic mice. During contact hypersensitivity, murine P-selectin messenger (m) RNA was up-regulated and P-selectin was essential for leukocyte recruitment. However, human P-selectin mRNA was down-regulated and P-selectin contributed much less to leukocyte recruitment. These findings reveal functionally significant differences in basal and inducible expression of human and murine P-selectin in vivo.
authors.affiliation: Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Zhenghui
authors.initials: Z
authors.lastname: Liu
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Miner
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Yago
authors.forename: Longbiao
authors.initials: L
authors.lastname: Yao
authors.forename: Florea
authors.initials: F
authors.lastname: Lupu
authors.forename: Lijun
authors.initials: L
authors.lastname: Xia
authors.forename: Rodger P
authors.initials: RP
authors.lastname: McEver
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D015153:Blotting, Western; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D036904:Leukocyte Rolling; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009504:Neutrophils / Q000378:metabolism; D019007:P-Selectin / Q000235:genetics* / Q000378:metabolism; D010538:Peritonitis / Q000139:chemically induced / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013864:Thioglycolates; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014699:Venules / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D019007:P-Selectin; C546937:SELP protein, human; D013864:Thioglycolates; D014409:Tumor Necrosis Factor-alpha