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. J. Cell. Physiol. 227: 351–360, 2012. © 2011 Wiley Periodicals, Inc.