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Stress-Activated Signaling Pathways Mediate the Stimulation of Pregnancy-Associated Plasma Protein-A Expression in Cultured Human Fibroblasts

Endocrine Research Unit (Z.T.R., L.K.B., C.A.C.), Division of Endocrinology, Metabolism, and Nutrition, Mayo Clinic College of Medicine, Rochester, Minnesota 55905; and Department of Molecular Biology (C.O.), University of Aarhus, 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) is an IGF binding protein protease that appears to function as a posttranslational modulator of IGF bioavailability in response to injury. A previous study indicated that the proinflammatory cytokines, TNF and IL-1ß, were potent stimulators of PAPP-A expression in cultured human fibroblasts. In this study, we investigated the intracellular signaling pathways mediating cytokine-stimulated PAPP-A expression. Treatment of human fibroblasts with TNF and IL-1ß (1 nM) had little or no effect on phosphatidylinositol 3-kinase and Erk1/2 activation, pathways commonly associated with proliferation. On the other hand, TNF and IL-1ß induced p38, c-Jun N-terminal kinase (JNK), and nuclear factor (NF)B activation, pathways more closely related to stress response. An inhibitor of p38 activation (SB203580) had no effect on TNF- or IL-1ß-stimulated PAPP-A expression. The JNK inhibitor, SP600125, had no effect on IL-1ß- or TNF-stimulated PAPP-A mRNA expression. However, SP600125 effectively inhibited IL-1ß-induced PAPP-A protein expression. MG-132, a proteasome inhibitor that blocked degradation of the intrinsic NFB inhibitor, IB, and thereby prevented NFB activation, was a potent inhibitor of both TNF- and IL-1ß-stimulated PAPP-A mRNA and protein expression and IGF binding protein-4 protease activity. MG-132 had no effect on JNK phosphorylation or p38 activation, and SB203580 and SP600125 had no effect on IB degradation, documenting inhibitor specificity. BAY11–7082, another inhibitor of NFB activation, also inhibited TNF- and IL-1ß-stimulated PAPP-A expression and IGF binding protein-4 protease activity. These data indicate that NFB activation is the primary mediator of cytokine-stimulated PAPP-A expression in human fibroblasts.

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