title: Growth differentiation factor-15: induction in liver injury through p53 and tumor necrosis factor-independent mechanisms.
abstract: Expression of macrophage inhibitory cytokine-1 (MIC-1), a divergent transforming growth factor-beta family member, and its murine ortholog, growth/differentiation factor-15 (GDF-15), is induced in hepatocytes by surgical and chemical injury and heat shock. Here, we demonstrate that the regulation of GDF-15/MIC-1 expression may be evolutionarily conserved because MIC-1 was induced in diseased human livers. Gdf15 induction was independent of protein synthesis, a hallmark of immediate-early gene regulation. Although tumor necrosis factor (TNF) induced GDF-15 expression, injury-elicited Gdf15 expression was not reduced in mice deficient for both TNF receptor subtypes. Furthermore, although the stress sensor p53 is known to induce GDF-15/MIC-1 expression, injury-elicited Gdf15 expression was unchanged in p53 null mice. Our results demonstrate that GDF-15 induction is an immediate early response to liver injury that can occur through TNF and p53 independent pathways.
authors.affiliation: DeWitt Daughtry Family Department of Surgery and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Zimmers
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Jin
authors.forename: Edward C
authors.initials: EC
authors.lastname: Hsiao
authors.forename: Eduardo A
authors.initials: EA
authors.lastname: Perez
authors.forename: Robert H
authors.initials: RH
authors.lastname: Pierce
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Chavin
authors.forename: Leonidas G
authors.initials: LG
authors.lastname: Koniaris
mesh_terms: D000818:Animals; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D017781:Genes, Immediate-Early / Q000502:physiology; D055436:Growth Differentiation Factor 15; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism* / Q000503:physiopathology*; D008115:Liver Regeneration / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016207:Cytokines; C526140:GDF15 protein, human; C526141:Gdf15 protein, mouse; D055436:Growth Differentiation Factor 15; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53