Brain microvessel endothelial cell responses to tumor necrosis factor-alpha involve a nuclear factor kappa B (NF-kappaB) signal transduction pathway.
The involvement of nuclear factor kappa B (NF-kappaB) in TNF-induced increases in cerebral microvascular permeability was evaluated both in vitro, using primary cultured bovine brain microvessel endothelial cells (BBMEC), and in vivo, using the rat cranial window model. In primary cultured BBMEC, TNF exposure resulted in an increased appearance of the Rel A subunit of NF-kappaB in immunoblots of cell lysates. Increases in the Rel A subunit of NF-kappaB were observed as early as 30-min after administration of TNF. The increased permeability and the secretion of prostaglandin E2 in response to TNF exposure in BBMEC monolayers were significantly reduced by several different NF-kappaB inhibitors, including PDTC, CAPE, BAY 11-7085, and lactacystin. Similar results were also obtained in the rat cranial window model where treatment with the COX-2 inhibitor, NS-398 (0.1 microM), or the NF-kappaB inhibitor, PDTC (10 microM), significantly reduced the permeability increases produced by TNF. These studies suggest that the increases in BBB permeability following TNF exposure are attributable to activation of an NF-kappaB-mediated signaling pathway in the cerebral microvasculature.
Trickler
W J
WJ
Department of Pharmaceutical Sciences, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, NE 68198-6025, USA.
Mayhan
W G
WG
Miller
D W
DW
D000818:Animals; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000166:cytology*; D002109:Caffeic Acids / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects; D002417:Cattle; D002478:Cells, Cultured; D003911:Dextrans / Q000493:pharmacokinetics; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D042783:Endothelial Cells / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D016328:NF-kappa B / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D020572:Oncogene Proteins v-rel / Q000378:metabolism; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D013450:Sulfones / Q000494:pharmacology; D013859:Thiocarbamates / Q000494:pharmacology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
C416282:BAY 11-7085; D002109:Caffeic Acids; D003911:Dextrans; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D009570:Nitriles; D020572:Oncogene Proteins v-rel; D013450:Sulfones; D013859:Thiocarbamates; D014409:Tumor Necrosis Factor-alpha; C066229:prolinedithiocarbamate; D011392:Proline; C055494:caffeic acid phenethyl ester; D015232:Dinoprostone; D010626:Phenylethyl Alcohol