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

Medizinische Kernklinik und Poliklinik, Universitats-Krankenhaus Eppendorf, Hamburg, Germany.

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 1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF-alpha), the present studies evaluated IL-1 beta and TNF-alpha 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-1 beta 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-1 beta and TNF-alpha, and at higher cytokine concentrations no stimulatory effects of GH were observed. Both IL-1 beta and TNF-alpha 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-1 beta and TNF-alpha inhibited GH-stimulated IGF-I synthesis. Diminished GH receptor mRNA concentrations in response to IL-1 beta and TNF-alpha 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-1 beta and TNF-alpha.

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