title: Cdc42 GTPases facilitate TNF-α-mediated secretion of CCL2 from peripheral nerve microvascular endoneurial endothelial cells.
abstract: Trafficking of autoreactive leukocytes across the blood-nerve barrier and into peripheral nerves is an early pathological hallmark of Guillain-Barré syndrome (GBS). Tumor necrosis factor-α (TNF-α), a proinflammatory cytokine, promotes transendothelial migration by upregulating endothelial expression of inflammatory mediators, including CCL2, a chemokine implicated in GBS. We sought to determine the mechanism by which TNF-α induces expression and secretion of CCL2 from peripheral nerve microvascular endoneurial endothelial cells (PNMECs). Expression of CCL2 mRNA and protein in quiescent PNMEC cultures was minimal. In contrast, cultures treated with TNF-α exhibited increased CCL2 mRNA and protein content, as well as protein secretion. Simvastatin significantly attenuated TNF-α-induced CCL2 secretion without affecting CCL2 mRNA or protein expression. Co-incubation with geranylgeranyl pyrophosphate, but not farnesyl pyrophosphate, prevented the effect of simvastatin. By comparison, inhibiting protein isoprenylation with GGTI-298, but not FTI-277, mimicked the effect of simvastatin and significantly attenuated transendothelial migration in vitro. Inhibition of the monomeric GTPase Cdc42, but not Rac1 or RhoA-C, attenuated TNF-α-mediated CCL2 secretion. TNF-α-mediated trafficking of autoreactive leukocytes into peripheral nerves during GBS may proceed by a mechanism that involves Cdc42-facilitated secretion of CCL2.
authors.affiliation: Research Service, Department of Veterans Affairs, Edward Hines, Jr. VA Hospital, Hines, IL, USA; Program of Neuroscience.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Langert
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Von Zee
authors.forename: Evan B
authors.initials: EB
authors.lastname: Stubbs
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007948:Leukemia, Monocytic, Acute / Q000473:pathology; D010525:Peripheral Nerves / Q000166:cytology*; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D054876:Prenylation / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011106:Polyisoprenyl Phosphates; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D020764:cdc42 GTP-Binding Protein; C002963:geranylgeranyl pyrophosphate
keywords: GTPases; cytokine; endothelial; microvascular; peripheral nerve
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