Temporal and spatial expression of IGF-I and IGFBP-1 during acute-phase response induced by localized inflammation in rats.

OBJECTIVE: The acute-phase response (APR), a cytokine-induced defense reaction of the body that enhances the innate immunity mechanisms directed to eliminate the noxious agent and restrict the area of damage, is accompanied by numerous alterations of the IGF axis. The liver is a central organ of both the IGF system and the APR because it releases most of IGF-I and IGFBP-1 in the circulation and is the main target organ for acute-phase-cytokines such as IL-6. METHODS: In the current work the expression of IGF-I and IGFBP-1 was studied in the liver and extrahepatic tissues in a rat model of localized inflammation induced by intramuscular injection of turpentine oil (TO). The mRNA expression of IGF-I and IGFBP-1 was determined by Northern blot analysis and quantitative RT-PCR. Circulating levels of IGF-I and IGFBP-1 were evaluated by radioimmunoassay and [(125)I]-IGF-I ligand blotting, respectively. RESULTS: Administration of TO to the rats led to a significant reduction of IGF-I gene expression in the liver and spleen. These changes were accompanied by a reduction of serum IGF-I concentrations to approximately 50% of levels observed in control rats. In contrast to IGF-I, IGFBP-1 mRNA expression was rapidly elevated in the livers of TO-treated rats. IGFBP-1 transcripts were already detectable at 30 min after TO injection and reached their maximal levels by 6h. IGFBP-1 gene expression was also increased in the kidneys. This elevation, however, was delayed and less prominent than in the liver. CONCLUSIONS: Our data demonstrate that localized inflammation induced by intramuscular TO injection is accompanied not only by decreased IGF-I but also by increased IGFBP-1 gene expression explaining at least in part the catabolic changes of metabolism observed during the acute-phase response.

The insulin-like growth factor system: IGFs, IGF-binding proteins and IGFBP-proteases.

Insulin-like growth factors (IGF-I/-II) are not only the endocrine mediators of growth hormone-induced metabolic and anabolic actions but also polypeptides that act in a paracrine and autocrine manner to regulate cell growth, differentiation, apoptosis and transformation. The IGF system is a complex network comprised of two growth factors (IGF-I and -II), cell surface receptors (IGF-IR and -IIR), six specific high affinity binding proteins (IGFBP-I to IGFBP-6), IGFBP proteases as well as several other IGFBP-interacting molecules, which regulate and propagate IGF actions in several tissues. Besides their broad-spectrum physiological and pathophysiological functions, recent evidence suggests even a link between IGFs and different malignancies.

Regulation of insulin-like growth factor-I and of insulin-like growth factor binding protein-1, -3 and -4 in cocultures of rat hepatocytes and Kupffer cells by interleukin-6.

BACKGROUND/AIMS: Catabolism is associated with decreased serum concentrations of insulin-like growth factor (IGF)-I and insulin-like growth factor binding protein (IGFBP)-3 associated with elevated IGFBP-3 protease activity and increased concentrations of IGFBP-1 and -4. The effects of the acute phase mediators interleukin (IL)-6, IL-1beta and tumor necrosis factor alpha (TNFalpha) on the biosynthesis of IGF-I and IGFBPs were studied in primary rat liver cells. METHODS: mRNA levels of IGF-I and of IGFBPs were analyzed by Northern blotting, secretion of IGFBPs by [(125)I]IGF-I ligand blotting. Proteolytic activity was measured using iodinated recombinant IGFBP-3 as the substrate. RESULTS: In hepatocytes, Kupffer cells (KC) and cocultures of hepatocytes with KC, IL-6 reduced IGF-I biosynthesis dose-dependently. IL-6 stimulated mRNA expression and protein secretion of IGFBP-1 and -4 in hepatocytes and that of IGFBP-3 in KC, respectively. In cocultures, biosynthesis of IGFBP-1, -3 and -4 was increased dose-dependently by IL-6, while the effects of IL-1beta or TNFalpha were less prominent. At neutral pH, proteolytic activity against IGFBP-3 was not detected in media of cocultures treated with IL-6. CONCLUSIONS: The alterations of IGF-I, IGFBP-1 and -4 observed in catabolism correlate with the effects of IL-6 on the biosynthesis of these components in primary rat liver cells, while a neutral IGFBP-3 protease was not detectable.