title: Divergent roles for p55 and p75 TNF-alpha receptors in the induction of plasminogen activator inhibitor-1.
abstract: Tumor necrosis factor-alpha (TNF-alpha) is elevated in obesity and in acute inflammatory states, and contributes to the elevated plasminogen activator inhibitor-1 (PAI-1) levels associated with these conditions. Mice genetically deficient in the p55 and p75 TNF-alpha receptors were used to study the roles of these receptors in the expression of PAI-1 in obese (ob/ob) mice, and in lean mice following acute stimulation with TNF-alpha. In ob/ob mice, p55 and p75 tumor necrosis factor-alpha receptors (TNFRs) act cooperatively to induce PAI-1 mRNA in most tissues, including the adipose tissue, kidney, heart, and liver. However, in lean mice, TNF-alpha-induced PAI-1 expression is mediated primarily by the p55 TNFR. Interestingly, PAI-1 mRNA expression in all tissues of the TNF-alpha-treated p75-deficient lean mice was significantly higher than that observed in TNF-alpha-treated wild-type mice. These observations suggest that the p75 TNFR may play a role in attenuating TNF-alpha-induced PAI-1 mRNA expression in acute inflammatory conditions. Our observation that soluble p75 TNFR was elevated in the plasma of TNF-alpha-treated mice in comparison to untreated mice supports this hypothesis. These studies thus provide insights into the TNF-alpha receptors involved in mediating and modulating the expression of PAI-1 in acute and chronic (eg, obesity) inflammatory states associated with elevated TNF-alpha.
authors.affiliation: Department of Cell Biology, Division of Vascular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Manjula
authors.initials: M
authors.lastname: Pandey
authors.forename: Gurol
authors.initials: G
authors.lastname: Tuncman
authors.forename: Gökhan S
authors.initials: GS
authors.lastname: Hotamisligil
authors.forename: Fahumiya
authors.initials: F
authors.lastname: Samad
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000097:blood / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese / Q000235:genetics; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics*; D018124:Receptors, Tumor Necrosis Factor / Q000097:blood / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014158:Transcription, Genetic
chemical_list: D015703:Antigens, CD; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II