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This version published online on December 4, 2003
Endocrinology, doi:10.1210/en.2003-1313
A more recent version of this article appeared on March 1, 2004
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Submitted on September 30, 2003
Accepted on November 24, 2003

PREGNANCY-ASSOCIATED PLASMA PROTEIN-A GENE EXPRESSION AS A TARGET OF INFLAMMATORY CYTOKINES

Zachary T. Resch1, Bing-Kun Chen1, Laurie K. Bale1, Claus Oxvig1, Michael T. Overgaard1, and Cheryl A. Conover1*

1 From The Division of Endocrinology, Metabolism, and Nutrition, Endocrine Research Unit, Mayo Clinic and Mayo Foundation, 200 First Street SW, 5-194 Joseph, Rochester, MN 55905 and Department of Molecular Biology, The University of Aarhus, Gustav Wieds Vej 10C, DK-8000, Aarhus C, Denmark.

* To whom correspondence should be addressed. E-mail: Conover.cheryl{at}mayo.edu.

Pregnancy-associated plasma protein-A (PAPP-A) cleaves insulin-like growth factor binding protein-4 (IGFBP-4), and appears to enhance local IGF bioavailability in response to injury. In this study, we determined the effect 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, tumor necrosis factor-{alpha} (TNF-{alpha}) and interleukin-1{beta} (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 media from TNF-{alpha}- and IL-1{beta}- treated (1 nM) cells and decreased 40% in media from IFN-{gamma}-treated (1 nM) cells. IGF-I-stimulated [3H]thymidine incorporation was significantly enhanced by pretreatment with 1 nM TNF-{alpha}, 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.
Key words: Pregnancy-associated plasma protein-A • Insulin-like growth factor binding protein-4 • Tumor necrosis factor-{alpha} • Interleukin-1{beta} • Interferon-{gamma} • Human fibroblasts




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