Inositoylated platelet-activating factor (Ino-C2-PAF) modulates dynamic lymphocyte-endothelial cell interactions and alleviates psoriasis-like skin inflammation in two complementary mouse models.

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.

• Authors: Susann Forkel, Margarete Schön, Annette Hildmann, Anna Claßen, Swen-Malte John, Kerstin Danker, Michael P Schön
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 134 Issue 10 Pg. 2510-2520 (Oct 2014) ISSN: 1523-1747 [Electronic] United States
• PMID: 24714204 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1-O-octadecyl-2-O-(2-inositolylethyl)-glycero-3-phosphatidylcholine
• E-Selectin
• JunB protein, mouse
• Platelet Activating Factor
• Proto-Oncogene Proteins c-jun
• Transcription Factors
• Transforming Growth Factor beta1
• Tumor Necrosis Factor-alpha
• Vascular Cell Adhesion Molecule-1
• Intercellular Adhesion Molecule-1
• Inositol

Topics

• Animals
• Apoptosis (drug effects)
• Cell Communication (drug effects)
• Cells, Cultured
• Disease Models, Animal
• E-Selectin (metabolism)
• Endothelium, Vascular (drug effects, pathology)
• Humans
• In Vitro Techniques
• Inositol (analogs & derivatives, pharmacology, therapeutic use)
• Intercellular Adhesion Molecule-1 (metabolism)
• Lymphocytes (drug effects, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Inbred ICR
• Mice, Knockout
• Platelet Activating Factor (analogs & derivatives, pharmacology, therapeutic use)
• Proto-Oncogene Proteins c-jun (deficiency, genetics)
• Psoriasis (drug therapy, genetics, metabolism)
• Transcription Factors (deficiency, genetics)
• Transforming Growth Factor beta1 (metabolism)
• Tumor Necrosis Factor-alpha (metabolism)
• Vascular Cell Adhesion Molecule-1 (metabolism)