TNF-alpha downregulates murine hepatic growth hormone receptor expression by inhibiting Sp1 and Sp3 binding

Children with chronic inflammatory diseases experience growth failure and w asting. This may be due to growth hormone resistance caused by cytokine-ind uced suppression of growth hormone receptor (GHR) gene expression. However, the factors governing inflammatory regulation of GHR are not known. We hav e reported that Sp1 and Sp3 regulate hepatic GHR expression. We hypothesize d that TNF-a suppresses GHR expression by inhibiting Sp1/Sp3 transactivator s. LPS administration significantly reduced murine hepatic GHR expression, as well as Spl and Sp3 binding to GHR promoter cis elements. TNF-a was inte gral to this response, as LPS did not affect hepatic Sp1/Sp3 binding or GHR expression in TNF receptor 1-deficient mice. TNF-alpha treatment of BNL CL .2 mouse liver cells reduced Spl and Sp3 binding to a GHR promoter cis elem ent and down regulated activity of a GHR promoter-driven luciferase reporte r. Combined mutations within adjacent Sp elements eliminated GHR promoter s uppression by TNF-a without affecting overall nuclear levels of Sp1 or Sp3 proteins. These studies demonstrate that murine GHR transcription is downre gulated by LPS, primarily via TNF-a-dependent signaling. Evidence suggests that inhibition of Sp transactivator binding is involved. Further investiga tion of these mechanisms may identify novel strategies for preventing infla mmatory suppression of growth.