Abstract
During catabolic diseases such as sepsis, inflammation, and infection, a state of growth hormone (GH) resistance develops in liver. This has been attributed in part to increased production of the proinflammatory cytokine interleukin-1beta (IL-1beta). To determine how IL-1beta induces GH resistance, we studied the acid-labile subunit (ALS) gene whose hepatic transcription is increased by GH via the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. IL-1beta reduced the ability of GH to stimulate ALS mRNA in rat primary hepatocytes and ALS promoter activity in H4-II-E rat hepatoma cells. This inhibition was dependent on ALSGAS1, an element resembling a gamma-interferon activated sequence that mediates the transcriptional effects of GH. Inhibition by IL-1beta was also associated with a reduction of GH-dependent binding of STAT5 to this element after chronic (8 and 24 h), but not after acute treatment (15 min). Because these results indicated that the inhibition by IL-1beta was indirect, expression of the recently discovered suppressors of cytokine action (SOCS) was examined in liver cells. IL-1beta did not alter the expression of SOCS1, SOCS2, and CIS, indicating that they are not involved. In contrast, IL-1beta increased SOCS3 mRNA by 8-fold after 24 h of treatment, whereas GH had no effect. Forced expression of SOCS3 was just as effective as IL-1beta in reducing the GH induction of ALS promoter activity in H4-II-E rat hepatoma cells. Similar results were observed in primary rat hepatocytes. We conclude that the induction of SOCS3 by IL-1beta contributes to the development of GH resistance in liver, and represents a mechanism by which cytokines such as IL-1beta cross-talk with cytokines using the JAK-STAT pathway.
Highlights
Natal animals, most of insulin-like growth factor (IGF)-I circulates in ternary complexes of 150 kDa composed of one molecule each of IGF-I, IGF-binding protein-3, or IGF-binding protein-5, and an acid-labile subunit (ALS) [3, 5, 6]
The H4-II-E rat hepatoma cells, which we have shown to recapitulate exactly the mechanisms leading to basal and growth hormone (GH)-stimulated transcription of the mouse ALS gene [11, 25], were transiently transfected with a luciferase construct driven by a promoter fragment corresponding to nt Ϫ703 to nt Ϫ11 (703WT) of the mouse ALS
This stimulation was suppressed by IL-1 in a dose-dependent manner with maximal inhibition of 43% at the dose of 10 ng/ml, similar to the concentration required for maximal inhibition of ALS mRNA in primary rat hepatocytes
Summary
Natal animals, most of IGF-I circulates in ternary complexes of 150 kDa composed of one molecule each of IGF-I, IGF-binding protein-3, or IGF-binding protein-5, and an acid-labile subunit (ALS) [3, 5, 6]. We have demonstrated that GH stimulates the transcription of the ALS gene in primary hepatocytes and in the H4-II-E hepatoma liver cell line by inducing the binding of signal transducer and activator of transcription (STAT)-5a and -5b to a single element resembling a ␥-interferon activated sequence (GAS) in the promoter [25].
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