Pregnancy-associated plasma protein a gene expression as a target of inflammatory cytokines

Endocrinology. 2004 Mar;145(3):1124-9. doi: 10.1210/en.2003-1313. Epub 2003 Dec 4.


Pregnancy-associated plasma protein A (PAPP-A) cleaves IGF-binding protein-4 (IGFBP-4) and appears to enhance local IGF bioavailability in response to injury. In this study we determined the effects of growth factors and cytokines involved in the healing process on PAPP-A expression in human dermal fibroblasts. There was no effect of platelet-derived growth factor, epidermal growth factor, or basic fibroblast growth factor on PAPP-A mRNA expression in these cells. However, treatment with the proinflammatory cytokines, TNFalpha and IL-1 beta, resulted in time- and dose-dependent increases in PAPP-A mRNA and protein expression (3- to 4-fold maximal effects), which were prevented by actinomycin D. On the other hand, interferon-gamma (IFN gamma) treatment markedly inhibited PAPP-A expression. IGFBP-4 proteolytic activity was increased 4-fold in medium from TNFalpha- and IL-1 beta-treated (1 nm) cells and decreased 40% in medium from IFN gamma-treated (1 nm) cells. IGF-I-stimulated [(3)H]thymidine incorporation was significantly enhanced by pretreatment with 1 nm TNFalpha, and this enhancement was blocked in the presence of protease-resistant IGFBP-4. In conclusion, PAPP-A expression is regulated by inflammatory cytokines in adult human fibroblasts, with functional consequences on IGFBP-4 protease activity and IGF-I bioavailability. These data provide a mechanism for the regulation of PAPP-A in response to injury and further implicate PAPP-A in the wound-healing processes.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Antineoplastic Agents / pharmacology*
  • Cells, Cultured
  • Dermis / cytology
  • Fibroblasts / cytology
  • Fibroblasts / physiology
  • Gene Expression / drug effects
  • Gene Expression / immunology
  • Growth Substances / pharmacology
  • Humans
  • Interferon-gamma / pharmacology
  • Interleukin-1 / pharmacology*
  • Pregnancy-Associated Plasma Protein-A / genetics*
  • Pregnancy-Associated Plasma Protein-A / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology*
  • Wound Healing / physiology


  • Antineoplastic Agents
  • Growth Substances
  • Interleukin-1
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma
  • Pregnancy-Associated Plasma Protein-A