Inositoylated platelet-activating factor (Ino-C2-PAF) modulates dynamic lymphocyte-endothelial cell interactions and alleviates psoriasis-like skin inflammation in two complementary mouse models.
Psoriasis, a tumor necrosis factor alpha (TNFα)-governed inflammatory disorder with prominent dysregulation of cutaneous vascular functions, has evolved into a model disorder for studying anti-inflammatory therapies. We present experimental in vitro and in vivo data on 1-O-octadecyl-2-O-(2-(myo-inositolyl)-ethyl)-sn-glycero-3-(R/S)-phosphatidyl-choline (Ino-C2-PAF), the lead compound of a class of synthetic glycosylated phospholipids, in anti-inflammatory therapy. Ino-C2-PAF strongly induced apoptosis only in TNFα-stimulated, but not in untreated human vascular endothelial cells. Moreover, TNFα-induced endothelial adhesion molecules that mediated the rolling and firm adhesion of leukocytes (vascular cell adhesion protein-1 (VCAM-1), E-selectin, and ICAM-1) were selectively downregulated by Ino-C2-PAF. Similarly, expression of L-selectin, VCAM-1 receptor α4β1 integrin , and lymphocyte function-associated antigen-1 on human peripheral blood mononuclear cells was reduced without induction of apoptosis. Functionally, these changes were accompanied by significant impairment of rolling and adhesion of human peripheral blood lymphocytes on TNFα-activated endothelial cells in a dynamic flow chamber system. When the therapeutic potential of Ino-C2-PAF was assessed in two complementary mouse models of psoriasis, K5.hTGFβ1 transgenic and JunB/c-Jun-deficient mice, Ino-C2-PAF led to significant alleviation of the clinical symptoms and normalized the pathological cutaneous changes including vascularization. There were no overt adverse effects. These findings suggested that Ino-C2-PAF is a potential candidate in the therapy of inflammatory skin diseases that include abnormal vascular functions.
Department of Dermatology, Venereology and Allergology, University Medical Center, Georg August University, Göttingen, Germany.
Susann
S
Forkel
Department of Dermatology, Venereology and Allergology, University Medical Center, Georg August University, Göttingen, Germany.
Margarete
M
Schön
Institute of Biochemistry, Charité University Medical Center, Berlin, Germany.
Annette
A
Hildmann
Department of Dermatology, Venereology and Allergology, University Medical Center, Georg August University, Göttingen, Germany; Lower Saxony Institute of Occupational Dermatology, University Medical Center Göttingen and University of Osnabrück, Osnabrück, Germany.
Anna
A
Claßen
Lower Saxony Institute of Occupational Dermatology, University Medical Center Göttingen and University of Osnabrück, Osnabrück, Germany; Department of Dermatology, Environmental Medicine and Health Care Theory, University of Osnabrück, Osnabrück, Germany.
Swen-Malte
SM
John
Institute of Biochemistry, Charité University Medical Center, Berlin, Germany.
Kerstin
K
Danker
Department of Dermatology, Venereology and Allergology, University Medical Center, Georg August University, Göttingen, Germany; Lower Saxony Institute of Occupational Dermatology, University Medical Center Göttingen and University of Osnabrück, Osnabrück, Germany. Electronic address: michael.schoen@med.uni-goettingen.de.
Michael P
MP
Schön
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002450:Cell Communication / Q000187:drug effects*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D019040:E-Selectin / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D066298:In Vitro Techniques; D007294:Inositol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D010972:Platelet Activating Factor / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D016755:Proto-Oncogene Proteins c-jun / Q000172:deficiency / Q000235:genetics; D011565:Psoriasis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
C587359:1-O-octadecyl-2-O-(2-inositolylethyl)-glycero-3-phosphatidylcholine; D019040:E-Selectin; C584097:JunB protein, mouse; D010972:Platelet Activating Factor; D016755:Proto-Oncogene Proteins c-jun; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D007294:Inositol