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Transforming growth factor-?1 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)-? is known to play a critical role in suppressing the immune response, and the TGF-?1 isoform is expressed in inflammatory cells. Thus, we wanted to investigate whether TGF-?1 could inhibit the expression of HO-1 during exposure to an inflammatory stimulus in macrophages. Here we demonstrate that TGF-?1 is able to downregulate LPS-induced HO-1 in mouse macrophages, and this reduction in HO-1 occurred through signaling of TGF-?1 via its type I receptor, and activation of Smad2. This TGF-?1 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-?1 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-?1 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.

SUBMITTER: Chung SW

PROVIDER: S-EPMC3132305 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Transforming growth factor-β1 suppression of endotoxin-induced heme oxygenase-1 in macrophages involves activation of Smad2 and downregulation of Ets-2.

Chung Su Wol SW Kwon Min-Young MY Kang Young-Ho YH Chung Hun-Taeg HT Lee Seon-Jin SJ Kim Hong Pyo HP Perrella Mark A MA

Journal of cellular physiology 20120101 1

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 p ...[more]

PMID: 21437904

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Project description:Macrophages are central for the immune control of intracellular microbes. Heme oxygenase 1 (HO-1, hmox) is the first and rate limiting enzyme in the breakdown of heme originating from degraded senescent erythrocytes and heme-proteins, yielding equal amounts of iron, carbon monoxide and biliverdin. HO-1 is strongly up-regulated in macrophages in response to inflammatory signals, including bacterial endotoxin. In view of the essential role of iron for the growth and proliferation of intracellular bacteria along with known effects of the metal on innate immune function, we examined whether HO-1 plays a role in the control of infection with the intracellular bacterium Salmonella Typhimurium. We studied the course of infection in stably-transfected murine macrophages (RAW264.7) bearing a tetracycline-inducible plasmid producing hmox shRNA and in primary HO-1 knockout macrophages. While uptake of bacteria into macrophages was not affected, a significantly reduced survival of intracellular Salmonella was observed upon hmox knockdown or pharmacological hmox inhibition, which was independent of Nramp1 functionality. This could be traced to limitation of iron availability for intramacrophage bacteria along with enhanced stimulation of innate immune effector pathways, including the formation of reactive oxygen and nitrogen species and increased TNF-α expression. Mechanistically, these latter effects result from intracellular iron limitation with subsequent activation of NF-κB and further inos, tnfa and p47phox transcription along with reduced formation of the anti-inflammatory and radical scavenging molecules, CO and biliverdin as a consequence of HO-1 silencing. Taken together our data provide novel evidence that the infection-driven induction of HO-1 exerts detrimental effects in the early control of Salmonella infection, whereas hmox inhibition can favourably modulate anti-bacterial immune effector pathways of macrophages and promote bacterial elimination.

Dataset Information

Transforming growth factor-?1 suppression of endotoxin-induced heme oxygenase-1 in macrophages involves activation of Smad2 and downregulation of Ets-2.

Publications

Transforming growth factor-β1 suppression of endotoxin-induced heme oxygenase-1 in macrophages involves activation of Smad2 and downregulation of Ets-2.

Similar Datasets

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