title: Stress-activated signaling pathways mediate the stimulation of pregnancy-associated plasma protein-A expression in cultured human fibroblasts.
abstract: 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, TNFalpha and IL-1beta, 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 TNFalpha and IL-1beta (1 nm) had little or no effect on phosphatidylinositol 3-kinase and Erk1/2 activation, pathways commonly associated with proliferation. On the other hand, TNFalpha and IL-1beta induced p38, c-Jun N-terminal kinase (JNK), and nuclear factor (NF)kappaB activation, pathways more closely related to stress response. An inhibitor of p38 activation (SB203580) had no effect on TNFalpha- or IL-1beta-stimulated PAPP-A expression. The JNK inhibitor, SP600125, had no effect on IL-1beta- or TNFalpha-stimulated PAPP-A mRNA expression. However, SP600125 effectively inhibited IL-1beta-induced PAPP-A protein expression. MG-132, a proteasome inhibitor that blocked degradation of the intrinsic NFkappaB inhibitor, IkappaB, and thereby prevented NFkappaB activation, was a potent inhibitor of both TNFalpha- and IL-1beta-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 IkappaB degradation, documenting inhibitor specificity. BAY11-7082, another inhibitor of NFkappaB activation, also inhibited TNFalpha- and IL-1beta-stimulated PAPP-A expression and IGF binding protein-4 protease activity. These data indicate that NFkappaB activation is the primary mediator of cytokine-stimulated PAPP-A expression in human fibroblasts.
authors.affiliation: Endocrine Research Unit, Division of Endocrinology, Metabolism, and Nutrition, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Zachary T
authors.initials: ZT
authors.lastname: Resch
authors.forename: Claus
authors.initials: C
authors.lastname: Oxvig
authors.forename: Laurie K
authors.initials: LK
authors.lastname: Bale
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Conover
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D002460:Cell Line; D005347:Fibroblasts / Q000201:enzymology*; D005786:Gene Expression Regulation; D006801:Humans; D007375:Interleukin-1 / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism*; D011266:Pregnancy-Associated Plasma Protein-A / Q000235:genetics / Q000378:metabolism*; D015290:Second Messenger Systems / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D018709:Statistics, Nonparametric; D013312:Stress, Physiological / Q000201:enzymology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: D007375:Interleukin-1; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D011266:Pregnancy-Associated Plasma Protein-A