Interleukin-1beta induces the expression of insulin-like growth factor binding protein-1 during decidualization in the primate.

Since interleukin (IL)-1 can modulate fetal/maternal interactions, we hypothesized that IL-1beta is one potential embryonic cytokine that regulates the conceptus-induced decidual response in baboon stromal fibroblasts. Treatment of stromal fibroblasts with IL-1beta (10 ng/ml, 10 min) resulted in the phosphorylation of p38 mitogen-activated protein kinase and IkappaB-alpha. This suggests that IL-1beta induces multiple signaling pathways in stromal cells that result in the activation of mitogen-activated protein kinase cascade and the transcription factor NF-kappaB. After 4 h of stimulation, IL-1beta induced gene expression of cyclooxygenase-2 (COX-2) but not cyclooxygenase-1 (COX-1). PGE2 synthesis paralleled COX-2 messenger RNA expression. The addition of hormones [36 nM estradiol-17beta, 1 microM medroxyprogesterone acetate, and 100 ng/ml relaxin] to IL-1beta-treated cells induced insulin-like growth factor binding protein-1 (IGFBP-1) messenger RNA expression after 3 days of incubation. A specific COX-2 inhibitor, NS 398 (10 nM), partially inhibited IGFBP-1 protein synthesis. In contrast, the induction of IGFBP-1 by N6, 2'-O-dibutyryladenosine 3:5'-cyclic monophosphate (dbcAMP) and hormones was not affected by NS 398 treatment. Both dbcAMP and IL-1beta, in the presence of hormones, can independently induce IGFBP-1 gene expression and decidualization. However, if IL-1beta and dbcAMP were added together, IGFBP-1 expression was inhibited. These data suggest that IL-1beta can activate multiple signaling pathways that either positively or negatively regulate IGFBP-1 gene expression and decidualization.