Heme oxygenase-1 regulates dendritic cell function through modulation of p38 MAPK-CREB/ATF1 signaling.
Dendritic cells (DCs) are critical for the initiation of immune responses including activation of CD8 T cells. Intracellular reactive oxygen species (ROS) levels influence DC maturation and function. Intracellular heme, a product of catabolism of heme-containing metalloproteins, is a key inducer of ROS. Intracellular heme levels are regulated by heme oxygenase-1 (HO-1), which catalyzes the degradation of heme. Heme oxygenase-1 has been implicated in regulating DC maturation; however, its role in other DC functions is unclear. Furthermore, the signaling pathways modulated by HO-1 in DCs are unknown. In this study, we demonstrate that inhibition of HO-1 activity in murine bone marrow-derived immature DCs (iDCs) resulted in DCs with raised intracellular ROS levels, a mature phenotype, impaired phagocytic and endocytic function, and increased capacity to stimulate antigen-specific CD8 T cells. Interestingly, our results reveal that the increased ROS levels following HO-1 inhibition did not underlie the changes in phenotype and functions observed in these iDCs. Importantly, we show that the p38 mitogen-activated protein kinase (p38 MAPK), cAMP-responsive element binding protein (CREB), and activating transcription factor 1 (ATF1) pathway is involved in the mediation of the phenotypic and functional changes arising from HO-1 inhibition. Furthermore, up-regulation of HO-1 activity rendered iDCs refractory to lipopolysaccharide-induced activation of p38 MAPK-CREB/ATF1 pathway and DC maturation. Finally, we demonstrate that treatment of iDC with the HO-1 substrate, heme, recapitulates the effects that result from HO-1 inhibition. Based on these results, we conclude that HO-1 regulates DC maturation and function by modulating the p38 MAPK-CREB/ATF1 signaling axis.
From the Medical Research Council (MRC) Centre for Drug Safety Science and Department of Molecular and Clinical Pharmacology, Sherrington Buildings, Ashton Street, University of Liverpool, Liverpool L69 3GE, United Kingdom and the Department of Pharmacology and Therapeutics, College of Medicine, Al-Qadisiyah University, P. O. Box 80, Diwaniyah 58001, Iraq.
Laith M A
LM
Al-Huseini
From the Medical Research Council (MRC) Centre for Drug Safety Science and Department of Molecular and Clinical Pharmacology, Sherrington Buildings, Ashton Street, University of Liverpool, Liverpool L69 3GE, United Kingdom and.
Han Xian
HX
Aw Yeang
From the Medical Research Council (MRC) Centre for Drug Safety Science and Department of Molecular and Clinical Pharmacology, Sherrington Buildings, Ashton Street, University of Liverpool, Liverpool L69 3GE, United Kingdom and.
Junnat M
JM
Hamdam
From the Medical Research Council (MRC) Centre for Drug Safety Science and Department of Molecular and Clinical Pharmacology, Sherrington Buildings, Ashton Street, University of Liverpool, Liverpool L69 3GE, United Kingdom and.
Swaminathan
S
Sethu
From the Medical Research Council (MRC) Centre for Drug Safety Science and Department of Molecular and Clinical Pharmacology, Sherrington Buildings, Ashton Street, University of Liverpool, Liverpool L69 3GE, United Kingdom and.
Naif
N
Alhumeed
From the Medical Research Council (MRC) Centre for Drug Safety Science and Department of Molecular and Clinical Pharmacology, Sherrington Buildings, Ashton Street, University of Liverpool, Liverpool L69 3GE, United Kingdom and.
Wai
W
Wong
From the Medical Research Council (MRC) Centre for Drug Safety Science and Department of Molecular and Clinical Pharmacology, Sherrington Buildings, Ashton Street, University of Liverpool, Liverpool L69 3GE, United Kingdom and Jean.Sathish@liv.ac.uk.
Jean G
JG
Sathish
D051697:Activating Transcription Factor 1 / Q000378:metabolism*; D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D051697:Activating Transcription Factor 1; C497100:Atf1 protein, mouse; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D051547:Heme Oxygenase-1; D048051:p38 Mitogen-Activated Protein Kinases
ATF1; CREB; Co-stimulation; Dendritic Cells; Heme Oxygenase; Reactive Oxygen Species (ROS); p38 MAPK