title: Plasma gelsolin modulates cellular response to sphingosine 1-phosphate.
abstract: Hypogelsolinemia is observed in patients with different states of acute or chronic inflammation such as sepsis, rheumatoid arthritis, and multiple sclerosis. In animal models of sepsis, repletion of plasma gelsolin reduces septic mortality. However, the functions of extracellular gelsolin and the mechanisms leading to its protective nature are poorly understood. Potential mechanisms involve gelsolin's extracellular actin scavenging function or its ability to bind bioactive lipids or proinflammatory mediators, which would limit inflammatory responses and prevent tissue damage. Here we report that human plasma gelsolin binds to sphingosine 1-phosphate (S1P), a pleiotropic cellular agonist involved in various immune responses, and to its synthetic structural analog FTY720P (Gilenya). The fluorescence intensity of a rhodamine B-labeled phosphatidylinositol 4,5-bisphosphate binding peptide derived from gelsolin and the optical density of recombinant human plasma gelsolin (rhpGSN) were found to decrease after the addition of S1P or FTY720P. Gelsolin's ability to depolymerize F-actin also decreased progressively with increasing addition of S1P. Transient increases in phosphorylation of extracellular signal-regulated kinase in bovine aortic endothelial cells (BAECs) after S1P treatment were inhibited by rhpGSN. The ability of S1P to increase F-actin content and the elastic modulus of primary astrocytes and BAECs was also prevented by rhpGSN. Evaluation of S1P and gelsolin levels in cerebrospinal fluid reveals a low concentration of gelsolin and a high concentration of S1P in samples obtained from patients suffering from lymphatic meningitis. These findings suggest that gelsolin-mediated regulation of S1P bioactivity may be important to maintain immunomodulatory balance at inflammatory sites.
authors.affiliation: Univ. of Pennsylvania, Inst. for Medicine and Engineering, 1010 Vagelos Research Laboratories, 3340 Smith Walk, Philadelphia, PA 19104, USA. buckirob@mail.med.upenn.edu
authors.forename: Robert
authors.initials: R
authors.lastname: Bucki
authors.forename: Alina
authors.initials: A
authors.lastname: Kulakowska
authors.forename: Fitzroy J
authors.initials: FJ
authors.lastname: Byfield
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Zendzian-Piotrowska
authors.forename: Marcin
authors.initials: M
authors.lastname: Baranowski
authors.forename: Michal
authors.initials: M
authors.lastname: Marzec
authors.forename: Jessamine P
authors.initials: JP
authors.lastname: Winer
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Ciccarelli
authors.forename: Jan
authors.initials: J
authors.lastname: Górski
authors.forename: Wieslaw
authors.initials: W
authors.lastname: Drozdowski
authors.forename: Robert
authors.initials: R
authors.lastname: Bittman
authors.forename: Paul A
authors.initials: PA
authors.lastname: Janmey
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases / Q000032:analysis / Q000378:metabolism; D018260:Gelsolin / Q000097:blood* / Q000134:cerebrospinal fluid / Q000378:metabolism; D006801:Humans; D008206:Lymphatic Diseases / Q000378:metabolism; D008246:Lysophospholipids / Q000134:cerebrospinal fluid / Q000378:metabolism*; D008581:Meningitis / Q000378:metabolism; D010755:Organophosphates / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000134:cerebrospinal fluid / Q000378:metabolism
chemical_list: D000199:Actins; C525008:FTY 720P; D018260:Gelsolin; D008246:Lysophospholipids; D010755:Organophosphates; C060506:sphingosine 1-phosphate; D048049:Extracellular Signal-Regulated MAP Kinases; D013110:Sphingosine
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