TY - JOUR
T1 - Pregnancy-Associated Plasma Protein a Gene Expression as a Target of Inflammatory Cytokines
AU - Resch, Zachary T.
AU - Chen, Bing Kun
AU - Bale, Laurie K.
AU - Oxvig, Claus
AU - Overgaard, Michael T.
AU - Conover, Cheryl A.
PY - 2004/3
Y1 - 2004/3
N2 - 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, TNFa and IL-1β, 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-γ (IFNγ) treatment markedly inhibited PAPP-A expression. IGFBP-4 proteolytic activity was increased 4-fold in medium from TNFα- and IL-1β-treated (1 nM) cells and decreased 40% in medium from IFNγ-treated (1 nM) cells. IGF-I-stimulated [3H]thymidine incorporation was significantly enhanced by pretreatment with 1 nM TNFα, 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.
AB - 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, TNFa and IL-1β, 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-γ (IFNγ) treatment markedly inhibited PAPP-A expression. IGFBP-4 proteolytic activity was increased 4-fold in medium from TNFα- and IL-1β-treated (1 nM) cells and decreased 40% in medium from IFNγ-treated (1 nM) cells. IGF-I-stimulated [3H]thymidine incorporation was significantly enhanced by pretreatment with 1 nM TNFα, 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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U2 - 10.1210/en.2003-1313
DO - 10.1210/en.2003-1313
M3 - Article
C2 - 14657012
AN - SCOPUS:1442348159
SN - 0013-7227
VL - 145
SP - 1124
EP - 1129
JO - Endocrinology
JF - Endocrinology
IS - 3
ER -