title: Transforming growth factor-β1 suppression of endotoxin-induced heme oxygenase-1 in macrophages involves activation of Smad2 and downregulation of Ets-2.
abstract: Heme oxygenase (HO)-1 is a cytoprotective molecule that is induced during the response to injury. An increase in HO-1 is an acute indicator of inflammation, and early induction of HO-1 has been suggested to correlate with severity of injury. While a great deal is known about the induction of HO-1 by inflammatory mediators and bacterial lipopolysaccharide (LPS), much less is known about the effects of anti-inflammatory mediators on HO-1 expression. Transforming growth factor (TGF)-β is known to play a critical role in suppressing the immune response, and the TGF-β1 isoform is expressed in inflammatory cells. Thus, we wanted to investigate whether TGF-β1 could inhibit the expression of HO-1 during exposure to an inflammatory stimulus in macrophages. Here we demonstrate that TGF-β1 is able to downregulate LPS-induced HO-1 in mouse macrophages, and this reduction in HO-1 occurred through signaling of TGF-β1 via its type I receptor, and activation of Smad2. This TGF-β1 response is dependent on an intact Ets-binding site (EBS) located 93 base pairs upstream from the mouse HO-1 transcription start site. This EBS is known to be important for Ets-2 transactivation of HO-1 by LPS stimulation, and we show that TGF-β1 is able to suppress LPS-induced Ets-2 mRNA and protein levels in macrophages. Moreover, silencing of Smad2 is able to prevent the suppression of both HO-1 and Ets-2 by TGF-β1 during exposure to LPS. These data suggest that the return of HO-1 to basal levels during the resolution of an inflammatory response may involve its downregulation by anti-inflammatory mediators.
authors: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. swchung@ulsan.ac.kr
authors: Su Wol
authors: SW
authors: Chung
authors: Min-Young
authors: MY
authors: Kwon
authors: Young-Ho
authors: YH
authors: Kang
authors: Hun-Taeg
authors: HT
authors: Chung
authors: Seon-Jin
authors: SJ
authors: Lee
authors: Hong Pyo
authors: HP
authors: Kim
authors: Mark A
authors: MA
authors: Perrella
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D015536:Down-Regulation; D004731:Endotoxins / Q000276:immunology / Q000633:toxicity; D004789:Enzyme Activation / Q000502:physiology; D020868:Gene Silencing; D051547:Heme Oxygenase-1 / Q000276:immunology / Q000378:metabolism*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D050787:Proto-Oncogene Protein c-ets-2 / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D051899:Smad2 Protein / Q000276:immunology / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000276:immunology / Q000378:metabolism*
chemical_list: D004731:Endotoxins; D050787:Proto-Oncogene Protein c-ets-2; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D053773:Transforming Growth Factor beta1; D051547:Heme Oxygenase-1