Heme oxygenase 1, nuclear factor E2-related
factor 2, and nuclear factor kappaB are involved
in hemin inhibition of type 2 cationic amino acid
transporter expression and L-Arginine transport
in stimulated macrophages.
Tsai PS, Chen CC, Tsai PS, Yang LC, Huang WY, Huang CJ.
Department of Anesthesiology, Mackay Memorial Hospital, Nursing and Management College, Taipei, Taiwan, Republic of China.
Comment in:
• Anesthesiology. 2007 Aug;107(2):355-6; author reply 356.
BACKGROUND: L-Arginine transport mediated by type 2 cationic amino acid transporter (CAT-2) is one crucial mechanism that regulates nitric oxide production mediated by inducible nitric oxide synthase. Heme oxygenase (HO)-1 induction has been reported to significantly attenuate inducible nitric oxide synthase expression and nitric oxide production. The authors sought to explore the effects of HO-1 induction on CAT-2 expression and L-arginine transport. The effects of HO-1 induction on nuclear factor E2-related factor 2 (Nrf2) and nuclear factor kappaB (NF-kappaB) were also investigated. METHODS: Murine macrophages (RAW264.7 cells) were randomized to receive
lipopolysaccharide, lipopolysaccharide plus hemin (an HO-1 inducer; 5, 50, or 500
microm), lipopolysaccharide plus hemin (5, 50, or 500 microm) plus tin protoporphyrin (an HO-1 inhibitor), or lipopolysaccharide plus hemin (5, 50, or 500 microm) plus hemoglobin (a carbon monoxide scavenger). Then, cell cultures were harvested and analyzed.
RESULTS: Lipopolysaccharide significantly induced Nrf2 activation and HO-1 expression. Lipopolysaccharide also significantly induced NF-kappaB activation, CAT-2 expression, and L-arginine transport. In a dose-dependent manner, hemin enhanced the
lipopolysaccharide-induced Nrf2 activation and HO-1 expression. In contrast, hemin, also in a dose-dependent manner, significantly attenuated the lipopolysaccharide-induced NF-kappaB activation, CAT-2 expression, and L-arginine transport. Furthermore, the effects of hemin were significantly reversed by both tin protoporphyrin and hemoglobin.
CONCLUSIONS: HO-1 induction significantly inhibited CAT-2 expression and L-arginine transport in lipopolysaccharide-stimulated macrophages, possibly through mechanisms involved activation of Nrf2 and inhibition of NF-kappaB. In addition, carbon monoxide mediated, at least in part, the effects of HO-1 induction on CAT-2 expression and L-arginine transport.