Antagonism of growth hormone by inflammation

The acute phase response (APR) is a stereotypic physiologic response to injury or infection. Cytokines released by monocytes and macrophages during the initial stages of an APR regulate the production of acute phase proteins. Hepatic expression of negative acute phase reactants, including several growth hormone (GH)-responsive genes, is temporarily antagonized as the liver reprioritizes protein production to accommodate synthesis of positive acute phase proteins. Understanding the mechanisms mediating these reproducible responses is of clinical importance; in chronic inflammation proper GH signaling is not restored. An example of the clinical manifestation of this is the observation that children with inflammatory disease often do not reach their full height potential.; The goal of this research was to explore the mechanisms for inhibition of GH signaling during an APR and to understand how specificity is attained. We examined these issues by studying regulation of the GH-responsive HNF6 gene, comparing the promoter regulation of the negative and positive acute phase reactants, Spi 2.1 and 2.2 and by exploring the cytokine-induced expression of a gene family implicated in suppression of cytokine signaling (SOCS) and monitoring their role in inhibiting GH signaling.; We show that endogenous HNF6 mRNA is induced by IL6, and addition of TNFα decreases GH or IL6-induced HNF6 expression. Further, we conclude that neither the GH nor IL6 response is mediated through gamma-activated sequence (GAS)-like elements (GLE) located in the HNF6 proximal promoter. Conversely, we demonstrate that the divergence in Spi 2.1 and 2.2 promoter regulation is achieved through STAT specificity at GLE rather than by a YY1 site or an NFκB binding site located within a 42 by insertion in the Spi 2.2 promoter.; Finally, we show that one mechanism for GH antagonism during an APR is through TNFα-induction of the SOCS family member, CIS, by NFκB CIS expression alone is sufficient to down-regulate GH-responsive expression of HNF6 and Spi 2.l. These data demonstrate a novel regulatory pathway for SOCS/CIS genes and provide a mechanism for modulation of GH responses during an APR.