Inositoylated Platelet-Activating Factor (Ino-C2-PAF) Modulates Dynamic Lymphocyte–Endothelial Cell Interactions and Alleviates Psoriasis-Like Skin Inflammation in Two Complementary Mouse Models View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2014-10

AUTHORS

Susann Forkel, Margarete Schön, Annette Hildmann, Anna Claßen, Swen-Malte John, Kerstin Danker, Michael P Schön

ABSTRACT

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. More... »

PAGES

2510-2520

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/jid.2014.170

    DOI

    http://dx.doi.org/10.1038/jid.2014.170

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1041811031

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/24714204


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