title: Pregnancy-associated plasma protein a gene expression as a target of inflammatory cytokines.
abstract: 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.
authors.affiliation: Division of Endocrinology, Metabolism, and Nutrition, Endocrine Research Unit, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
authors.forename: Zachary T
authors.initials: ZT
authors.lastname: Resch
authors.forename: Bing-Kun
authors.initials: BK
authors.lastname: Chen
authors.forename: Laurie K
authors.initials: LK
authors.lastname: Bale
authors.forename: Claus
authors.initials: C
authors.lastname: Oxvig
authors.forename: Michael T
authors.initials: MT
authors.lastname: Overgaard
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Conover
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D020405:Dermis / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D011266:Pregnancy-Associated Plasma Protein-A / Q000235:genetics* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014945:Wound Healing / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D006133:Growth Substances; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D011266:Pregnancy-Associated Plasma Protein-A