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The isoprostane 8‐iso‐PGF 2α suppresses monocyte adhesion to human microvascular endothelial cells via two independent mechanisms
Author(s) -
Kumar Anila,
Kingdon Edward,
Norman Jill
Publication year - 2005
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.03-1364fje
Subject(s) - chemistry , monocyte , isoprostane , umbilical vein , endothelial stem cell , cell adhesion , inflammation , oxidative stress , microbiology and biotechnology , adhesion , endocrinology , medicine , lipid peroxidation , immunology , biology , biochemistry , in vitro , organic chemistry
Isoprostanes, produced in vivo by non‐enzymatic free‐radical‐induced lipid peroxidation, are markers of oxidative stress. Elevated serum and urine levels of 8‐iso‐PGF 2α have been reported in a variety of diseases, many of which are characterized by early perivascular inflammatory infiltrates. It has been suggested that, in addition to being markers of oxidative stress, isoprostanes may have pathogenic functions. In this study, we investigated the potential role of 8‐iso‐PGF 2α in inflammation, focusing on its effects on adhesion of monocytes to microvascular endothelial cells, an early event in the inflammatory response. In monocyte adhesion assays, 8‐iso‐PGF 2α (>10 −8 M) suppressed both basal and TNF‐α‐induced monocyte adhesion to quiescent or proliferating human dermal (HMEC) and rat renal microvascular endothelial cells. In contrast, 8‐iso‐PGF 2α stimulated monocyte adhesion to human umbilical vein endothelial cells (HUVEC) as also reported by others. 8‐Iso‐PGF 2α had no effect on the viability (Trypan Blue exclusion) of U937 monocytes or HMEC. 8‐Iso‐PGF 2α also had no effect on HMEC surface expression of ICAM‐1 or VCAM‐1. Exposure of HMEC to 8‐iso‐PGF 2α for 1–2 h was sufficient to reduce monocyte adhesion to the cell surface, and this effect was independent of de novo protein synthesis by HMEC. The effect of 8‐iso‐PGF 2α was mimicked by a thromboxane receptor (TP) agonist (U46619) and blocked by a TP antagonist (SQ29548), indicating a TP‐mediated process. Signal transduction pathway inhibitors (SB203580, curcumin, and PD98059) implicated p38 and JNK, but not ERK, in 8‐iso‐PGF 2α ‐induced suppression of monocyte adhesion. In addition to a direct effect, conditioned medium (CM) transfer experiments suggest that 8‐iso‐PGF 2α induces a secondary mediator, which also suppresses monocyte adhesion but via an alternative mechanism initiated between 3–4 h, which is TP‐independent, requires new protein synthesis, and is primarily dependent on activation of p38. The data show that 8‐iso‐PGF 2α can suppress the attachment of monocytes to HMECs via two independent pathways, indicating a potential anti‐inflammatory effect of 8‐iso‐PGF 2α in the microvasculature.