Divergent roles for p55 and p75 TNF-alpha receptors in the induction of plasminogen activator inhibitor-1

Am J Pathol. 2003 Mar;162(3):933-41. doi: 10.1016/s0002-9440(10)63888-6.


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.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Antigens, CD / blood
  • Antigens, CD / genetics
  • Antigens, CD / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Obese / genetics
  • Plasminogen Activator Inhibitor 1 / blood
  • Plasminogen Activator Inhibitor 1 / genetics*
  • RNA, Messenger / genetics*
  • Receptors, Tumor Necrosis Factor / blood
  • Receptors, Tumor Necrosis Factor / deficiency
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor / physiology*
  • Receptors, Tumor Necrosis Factor, Type I
  • Receptors, Tumor Necrosis Factor, Type II
  • Transcription, Genetic


  • Antigens, CD
  • Plasminogen Activator Inhibitor 1
  • RNA, Messenger
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type I
  • Receptors, Tumor Necrosis Factor, Type II