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(American Journal of Pathology. 2003;162:933-941.)
© 2003 American Society for Investigative Pathology

Divergent Roles for p55 and p75 TNF- Receptors in the Induction of Plasminogen Activator Inhibitor-1

Manjula Pandey^*, Gurol Tuncman, Gökhan S. Hotamisligil and Fahumiya Samad^*

From the Department of Cell Biology, Division of Vascular Biology,^* The Scripps Research Institute, La Jolla, California; and the Department of Nutrition and Division of Biological Sciences, Harvard School of Public Health, Boston, Massachusetts

Tumor necrosis factor- (TNF-) 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- 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-. In ob/ob mice, p55 and p75 tumor necrosis factor- 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--induced PAI-1 expression is mediated primarily by the p55 TNFR. Interestingly, PAI-1 mRNA expression in all tissues of the TNF--treated p75-deficient lean mice was significantly higher than that observed in TNF--treated wild-type mice. These observations suggest that the p75 TNFR may play a role in attenuating TNF--induced PAI-1 mRNA expression in acute inflammatory conditions. Our observation that soluble p75 TNFR was elevated in the plasma of TNF--treated mice in comparison to untreated mice supports this hypothesis. These studies thus provide insights into the TNF- receptors involved in mediating and modulating the expression of PAI-1 in acute and chronic (eg, obesity) inflammatory states associated with elevated TNF-.

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