The liver is a major site of synthesis for insulin-like growth factor binding protein (IGFBP)-1. Because IGFBP-1 inhibits many anabolic actions of IGF-I, increases in IGFBP-1 may be partly responsible for the decrease in lean body mass observed in catabolic/inflammatory conditions. This study aimed to determine in Hep G2 cells 1) the sensitivity of IGFBP-1 synthesis to treatment with interleukin (IL)-1, tumor necrosis factor- (TNF-), and IL-6, 2) the ability of reactive oxygen species (ROS) to enhance IGFBP-1 production, and 3) the role of ROS in mediating cytokine-induced increases in IGFBP-1. Hep G2 cells responded to IL-1, TNF-, and IL-6 with maximal 8- to 10-fold increases in IGFBP-1 production. Although the maximal responsiveness of cells treated with TNF- and IL-6 was 20-30% less than that with IL-1, cells demonstrated a similar sensitivity to all cytokines (half-maximal responsive dose of ~10 ng/ml). A low concentration (3 ng/ml) of all three cytokines had an additive effect on IGFBP-1 production. Cytokines also increased IGFBP-1 mRNA. The half-life of IGFBP-1 mRNA was ~4 h and not altered by IL-1. Incubation with ROS, including H₂O₂ and nitric oxide (NO) donors, resulted in a relatively smaller increase in IGFBP-1. However, preincubating Hep G2 cells with various free radical scavengers and NO synthase and eicosanoid inhibitors failed to prevent or attenuate cytokine-induced increases in IGFBP-1. Finally, preincubating cells with pyrrolidinedithiocarbamate (PDTC) but not SN50 (inhibitors of nuclear factor-B activation and nuclear translocation, respectively) attenuated increases in IGFBP-1 induced by IL-1. These results indicate that 1) proinflammatory cytokines directly enhance IGFBP-1 synthesis by stimulating transcription without altering mRNA stability, 2) addition of exogenous ROS also stimulates IGFBP-1 production but to a smaller extent than cytokines, and 3) the cytokine-induced increase in IGFBP-1 production is not mediated by endogenous production of ROS or eicosanoids but appears to at least partially involve a PDTC-sensitive pathway.

tumor necrosis factor-; interleukins-1 and -6; free radicals; nitric oxide; nuclear factor-B; liver; insulin-like growth factor

This article has been cited by other articles:

				T.P. Neuvians, D. Schams, B. Berisha, and M.W. Pfaffl Involvement of Pro-Inflammatory Cytokines, Mediators of Inflammation, and Basic Fibroblast Growth Factor in Prostaglandin F2{alpha}-Induced Luteolysis in Bovine Corpus Luteum Biol Reprod, February 1, 2004; 70(2): 473 - 480. [Abstract] [Full Text] [PDF]

				S.-E. Kong, S. M. Firth, R. C. Baxter, and P. J. D. Delhanty Regulation of the acid-labile subunit in sustained endotoxemia Am J Physiol Endocrinol Metab, October 1, 2002; 283(4): E692 - E701. [Abstract] [Full Text] [PDF]

				J. Nygren, C. Carlsson-Skwirut, K. Brismar, A. Thorell, O. Ljungqvist, and P. Bang Insulin infusion increases levels of free IGF-I and IGFBP-3 proteolytic activity in patients after surgery Am J Physiol Endocrinol Metab, October 1, 2001; 281(4): E736 - E741. [Abstract] [Full Text] [PDF]

				V. J. Thannickal and B. L. Fanburg Reactive oxygen species in cell signaling Am J Physiol Lung Cell Mol Physiol, December 1, 2000; 279(6): L1005 - L1028. [Abstract] [Full Text] [PDF]

				C. H. Lang, X. Liu, G. J. Nystrom, and R. A. Frost Acute response of IGF-I and IGF binding proteins induced by thermal injury Am J Physiol Endocrinol Metab, June 1, 2000; 278(6): E1087 - E1096. [Abstract] [Full Text] [PDF]