Role of the Suppressor of Cytokine Signaling-3 in Mediating the Inhibitory Effects of Interleukin-1β on the Growth Hormone-dependent Transcription of the Acid-labile Subunit Gene in Liver Cells

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-1␤ (IL-1␤). To determine how IL-1␤ 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-1␤ 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 ␥-interferon activated sequence that mediates the transcriptional effects of GH. Inhibition by IL-1␤ 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-1␤ was indirect, expression of the recently discovered suppressors of cytokine action (SOCS) was examined in liver cells. IL-1␤ did not alter the expression of SOCS1, SOCS2, and CIS, indicating that they are not involved. In contrast, IL-1␤ 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-1␤ 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-1␤ contributes to the development of GH resistance in liver, and represents a mechanism by which cytokines such as IL-1␤ cross-talk with cytokines using the JAK-STAT pathway.

Impaired JAK-STAT signal transduction contributes to growth hormone resistance in chronic uremia

“…These changes were accompanied by an acute increase in SOCS-3 and CIS, and to a lesser degree SOCS-2 expression, findings confirmed by others (45). These studies are supported by in vitro data that indicates that proinflammatory cytokines such as IL-6 and IL-1β released during an endotoxin challenge may stimulate SOCS as part of an autoinhibitory intracellular feedback loop, causing concomitant GH resistance (43,45,46). This is another example where sensitivity to some cytokines is maintained, despite resistance to GH.…”

IGF-I, IGF-I-binding proteins and GH-binding protein in malnourished elderly patients with inflammation receiving refeeding therapy

“…First, the proinflammatory cytokines IL-1b, IL-6 and TNF-a inhibit expression of the IGF-I gene (44,45), and low circulating IGF-I concentration may be caused by a direct effect of cytokines in the liver. This effect may involve suppression of cytokine signaling inhibition of GH signaling by proinflammatory cytokines (46,47). Secondly, plasma IGF-I levels may be affected by proteolysis of IGFBP-3, the principal carrier protein of IGF-I.…”

The role of biomarkers in evaluating human health concerns from fungal contaminants in food

“…Recently, DON exposure in mice was associated with decreased IGF acid-labile subunit (161) , a binding protein of IGF-1 known to be critical for growth (162,163) . DON-induced decreases in IGF acid-labile subunit may lead to alterations in the growth hormone system and subsequent growth suppression.…”