Glial response to lipopolysaccharide: possible role of endothelins.
Glial inflammation plays a major role in the development of neurodegenerative diseases. Although endothelins (ETs) are known as modulators of inflammation in the periphery, little is known about their possible role in brain inflammation. Previously, we demonstrated that all three endothelins (ET-1, ET-2 and ET-3) enhanced unstimulated synthesis of the glial pro-inflammatory mediators, prostaglandin E₂ (PGE₂) and nitric oxide (NO). In the present study, glial cells were stimulated in an in vitro model of inflammation by incubation with the bacterial endotoxin lipopolysaccharide (LPS). Indeed, the present study shows that ETs regulate basal and LPS-induced glial inflammation in an opposite fashion. Here we demonstrate that ETs significantly inhibited the LPS-induced glial synthesis of PGE₂ and NO, and each of the selective antagonists for ETA and ETB receptors (BQ123 and BQ788 respectively), significantly inhibited the ETs effects in LPS-treated cells. Similar results were observed when expression of key enzymes namely, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in PG and NO synthesis respectively, was measured. ET-1 significantly enhanced the expression of both COX-2 and iNOS. Whereas, it inhibited the LPS-induced expression of both enzymes. These observations suggest a novel neuro-immune feedback pathway through which inflammatory mediators' synthesis is initially enhanced by ETs and are eventually blocked by the same neuropeptide when excessive production of inflammatory mediators occurs following an inflammatory insult.
Filipovich-Rimon
Talia
T
Department of Clinical Pharmacology, Ben-Gurion University, P.O.B. 653, Beer-Sheva 84105, Israel.
Fleisher-Berkovich
Sigal
S
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D019333:Endothelin-2 / Q000494:pharmacology; D016232:Endothelins / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D019333:Endothelin-2; D016232:Endothelins; D008070:Lipopolysaccharides; D010456:Peptides, Cyclic; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D015232:Dinoprostone; C072247:cyclo(Trp-Asp-Pro-Val-Leu)