title: Glucagon counteracts interleukin-6-dependent gene expression by redundant action of Epac and PKA.
abstract: Inflammation is the biological response to injurious stimuli. In the initial phase of the inflammatory process, interleukin-6 (IL-6) is the main inducer of acute phase protein expression in the liver. A prolonged acute phase response is characterised by a disturbed glucose homeostasis and elevated levels of IL-6, insulin, and counterregulatory hormones such as glucagon. Several studies deal with the impact of IL-6 on glucagon-dependent gene expression. In contrast, only very little is known about the influence of G-protein-coupled receptors on IL-6 signalling. Therefore, the aim of this study is to elucidate the regulation of IL-6-induced gene expression by glucagon. We could reveal a novel mechanism of negative regulation of IL-6-induced MAP kinase activation by glucagon in primary murine hepatocytes. IL-6-dependent induction of the ERK-dependent target gene Tfpi2, coding for a Kunitz-type serine protease inhibitor, was strongly down-regulated by glucagon treatment. Studying the underlying mechanism revealed a redundant action of the signalling molecules exchange protein activated by cyclic AMP (Epac) and protein kinase A. The metabolic hormone glucagon interferes in IL-6-induced gene expression. This observation is indicative for a regulatory role of G-protein-coupled receptors in the IL-6-dependent inflammatory response.
authors: Department of Biochemistry and Molecular Biology, RWTH Aachen University, Pauwelsstraße 30, D-52074 Aachen, Germany.
authors: Christina
authors: C
authors: Khouri
authors: Anna
authors: A
authors: Dittrich
authors: Sara Dutton
authors: SD
authors: Sackett
authors: Bernd
authors: B
authors: Denecke
authors: Christian
authors: C
authors: Trautwein
authors: Fred
authors: F
authors: Schaper
mesh_terms: D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D005934:Glucagon / Q000494:pharmacology*; D006023:Glycoproteins / Q000235:genetics; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D015398:Signal Transduction / Q000187:drug effects; D000093242:Interleukin-6 Inhibitors
chemical_list: D017868:Cyclic AMP-Dependent Protein Kinases; D005934:Glucagon; D006023:Glycoproteins; D020662:Guanine Nucleotide Exchange Factors; D015850:Interleukin-6; D000093242:Interleukin-6 Inhibitors; C482601:Epac protein, mouse; C021240:tissue-factor-pathway inhibitor 2