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Pregnancy-Associated Plasma Protein A Gene Expression as a Target of Inflammatory Cytokines

Division of Endocrinology, Metabolism, and Nutrition, Endocrine Research Unit, Mayo Clinic and Mayo Foundation (Z.T.R., B.-K.C., L.K.B., C.A.C.), Rochester, Minnesota 55905; and Department of Molecular Biology, University of Aarhus (C.O., M.T.O.), DK-8000 Aarhus C, Denmark

Address all correspondence and requests for reprints to: Cheryl A. Conover, Ph.D., Mayo Clinic, 200 First Street SW, 5-194 Joseph, Rochester, Minnesota 55905. E-mail: conover.cheryl{at}mayo.edu.

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, TNF and IL-1ß, 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- (IFN) treatment markedly inhibited PAPP-A expression. IGFBP-4 proteolytic activity was increased 4-fold in medium from TNF- and IL-1ß-treated (1 nM) cells and decreased 40% in medium from IFN-treated (1 nM) cells. IGF-I-stimulated [³H]thymidine incorporation was significantly enhanced by pretreatment with 1 nM TNF, 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.

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