Nuclear Factor κB Mediates the Inhibitory Effects of Interleukin-1 on Growth Hormone-Inducible Gene Expression

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Abstract

Background:

Hepatic expression of growth hormone (GH)-inducible genes serine protease inhibitor (Spi 2.1) and insulin-like growth factor (IGF)-I are inhibited by interleukin (IL)-1. The current study examines the role of the nuclear factor κB (NFκB) pathway and suppressor of cytokine signaling (SOCS)-3 expression as potential mechanisms for IL-1-mediated GH resistance.

Methods:

CWSV-1 hepatocytes were cotransfected with Spi 2.1 or IGF-1 promoter luciferase constructs and empty pCMV4 vector or dominant negative inhibitor-κBα (IκBα)S/A construct. Cells were treated with or without IL-1 and then stimulated with or without recombinant human GH. Cell extracts were assayed for luciferase activity and protein, normalized and expressed as fold-induction. CWSV-1 cells transfected with pCMV4 or IκBαS/A were treated with or without IL-1 then SOCS-3 mRNA was measured. Finally, CWSV-1 cells were cotransfected with a SOCS-3 promoter construct with or without pCMV4 or IκBαS/A and then stimulated with or without IL-1 to investigate SOCS-3 promoter activity.

Results:

CWSV-1 cells cotransfected with pCMV4 demonstrated a three- to fivefold induction of Spi 2.1 or IGF-1 promoter activity after GH stimulation that was almost completely inhibited by IL-1. Cotransfection with IκBαS/A increased GH-inducible Spi 2.1 and IGF-1 promoter activity, but the inhibitory effects of IL-1 on both promoters were attenuated by cotransfection with IκBαS/A. IL-1 stimulated SOCS-3 mRNA expression and promoter activity. Cotransfection with IκBαS/A increased IL-1-inducible SOCS-3 promoter activity, but not SOCS-3 mRNA or protein.

Conclusions:

Signaling via the NFκB pathway is responsible for the inhibitory effects of IL-1 on GH-inducible gene expression by a mechanism that does not seem to involve increased SOCS-3 expression.

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