Proinflammatory cytokines interleukin 1β and tumor necrosis factor α inhibit growth hormone stimulation of insulin-like growth factor I synthesis and growth hormone receptor mRNA levels in cultured rat liver cells

• Published in: European journal of endocrinology Vol. 135; no. 6; pp. 729 - 737
• Main Authors: WOLF, M, BÖHM, S, BRAND, M, KREYMANN, G
• Format: Journal Article
• Language: English
• Published: Colchester Portland Press 01.12.1996
• Subjects: Animals; Base Sequence; Biological and medical sciences; Cell physiology; Cells, Cultured; DNA Primers - chemistry; Dose-Response Relationship, Drug; EXPERIMENTAL STUDIES; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Human Growth Hormone - pharmacology; Humans; Insulin-Like Growth Factor I - analysis; Insulin-Like Growth Factor I - biosynthesis; Insulin-Like Growth Factor I - drug effects; Insulin-Like Growth Factor I - genetics; Interleukin-1 - pharmacology; Liver - cytology; Liver - drug effects; Liver - physiology; Male; Molecular and cellular biology; Polymerase Chain Reaction; Proteins - analysis; Radioimmunoassay; Rats; Rats, Wistar; Receptors, Somatotropin - drug effects; Receptors, Somatotropin - genetics; Recombinant Proteins - pharmacology; Responses to growth factors, tumor promotors, other factors; RNA, Messenger - analysis; RNA, Messenger - genetics; Tumor Necrosis Factor-alpha - pharmacology; Cell culture; Rat; STH; Cytokine; Rodentia; Interleukin 1β; Stimulation; Biosynthesis; Inflammation; Insulin like growth factor 1; In vitro; Biological activity; Protein hormone; Target tissue resistance; Vertebrata; Mammalia; Messenger RNA; Adenohypophyseal hormone; Animal; Hormonal regulation; Metabolic interrelation; Tumor necrosis factor α; Hormonal receptor
• ISSN: 0804-4643; 1479-683X
• DOI: 10.1530/eje.0.1350729

Wolf M, Böhm S, Brand M, Kreymann G. Proinflammatory cytokines interleukin 1β and tumor necrosis factor α inhibit growth hormone stimulation of insulin-like growth factor I synthesis and growth hormone receptor mRNA levels in cultured rat liver cells. Eur J Endocrinol 1996;135:729–37. ISSN 0804–4643 Low levels of insulin-like growth factor I (IGF-I) in critical illness are observed despite increased or normal levels of growth hormone (GH). The mechanisms for this apparent GH resistance have not been elucidated. As many of the acute inflammatory responses in critical illness are mediated by the proinflammatory cytokines interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α), the present studies evaluated IL-1β and TNF-α effects on steady-state and GH-stimulated IGF-I synthesis and GH receptor mRNA levels. In rat hepatocytes in primary culture, IGF-I released into culture medium was determined by radioimmunoassay, and quantitative competitive polymerase chain reaction was used to measure IGF-I mRNA and GH receptor mRNA concentrations. Growth hormone increased GH receptor mRNA, IGF-I mRNA and IGF-I protein secreted into the culture medium. In cells not stimulated with GH, modest inhibitory effects of IL-1β on GH receptor mRNA, IGF-I mRNA and IGF-I protein levels were seen. However, the stimulatory effects of GH were inhibited in a dose-dependent manner both by IL-1β and TNF-α, and at higher cytokine concentrations no stimulatory effects of GH were observed. Both IL-1β and TNF-α in submaximal dose had additive inhibitory effects on IGF-I protein concentrations but these effects did not result in irreversible damage to cells, as indicated by restoration of IGF-I and GH receptor mRNA levels to normal after withdrawal of cytokines. In conclusion, we demonstrated that in rat hepatocytes in primary culture IL-1β and TNF-α inhibited GH-stimulated IGF-I synthesis. Diminished GH receptor mRNA concentrations in response to IL-1β and TNF-α indicate that low IGF-I levels during severe illness, despite high circulating GH levels, may at least partially be a consequence of suppression of hepatic GH receptor synthesis by IL-1β and TNF-α. Matthias Wolf, Medizinische Kern- und Poliklinik, Universitäts-Krankenhaus Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany