Pathogen-Induced Interleukin-1β Processing and Secretion Is Regulated by a Biphasic Redox Response1

In this study, we show that IL-1β processing and secretion induced by pathogen-associated molecular pattern (PAMP) molecules in human monocytes is regulated by a biphasic redox event including a prompt oxidative stress and a delayed antioxidant response. Namely, PAMPs induce an early generation of reactive oxygen species (ROS) followed by increase of intracellular thioredoxin and release of reduced cysteine: this antioxidant phase is paralleled by secretion of mature IL-1β. ROS production and antioxidant response are both required, because either inhibitors of NADPH oxidase and of thioredoxin reductase impair IL-1β secretion. These inhibitors also hinder cysteine release and consequently prevent reduction of the extracellular medium: addition of exogenous reducing agents restores IL-1β secretion. Not only silencing of thioredoxin, but also of the ROS scavenger superoxide dismutase 1 results in inhibition of IL-1β secretion. Thus, PAMP-induced ROS trigger an antioxidant response involving intracellular redox enzymes and release of cysteine, ultimately required for IL-1β processing and secretion.

[1]  A. Rubartelli,et al.  DAMPs and inflammatory processes: the role of redox in the different outcomes , 2009, Journal of leukocyte biology.

[2]  R. Sitia,et al.  Stress as an intercellular signal: the emergence of stress-associated molecular patterns (SAMP). , 2008, Antioxidants & redox signaling.

[3]  S. Ferrini,et al.  The redox state of the lung cancer microenvironment depends on the levels of thioredoxin expressed by tumor cells and affects tumor progression and response to prooxidants , 2008, International journal of cancer.

[4]  H. Kwon,et al.  The non-provitamin A carotenoid, lutein, inhibits NF-kappaB-dependent gene expression through redox-based regulation of the phosphatidylinositol 3-kinase/PTEN/Akt and NF-kappaB-inducing kinase pathways: role of H(2)O(2) in NF-kappaB activation. , 2008, Free radical biology & medicine.

[5]  A. Rubartelli,et al.  The thiol redox state of lymphoid organs is modified by immunization: Role of different immune cell populations , 2008, European journal of immunology.

[6]  F. Meissner,et al.  Superoxide dismutase 1 regulates caspase-1 and endotoxic shock , 2008, Nature Immunology.

[7]  Andrew G. Watts,et al.  A Key Role for Redox Signaling in Rapid P2X7 Receptor-Induced IL-1β Processing in Human Monocytes1 , 2008, The Journal of Immunology.

[8]  A. Rubartelli,et al.  ATP is released by monocytes stimulated with pathogen-sensing receptor ligands and induces IL-1β and IL-18 secretion in an autocrine way , 2008, Proceedings of the National Academy of Sciences.

[9]  J. Tschopp,et al.  Innate Immune Activation Through Nalp3 Inflammasome Sensing of Asbestos and Silica , 2008, Science.

[10]  S. Akira,et al.  ASK1‐p38 MAPK‐p47phox activation is essential for inflammatory responses during tuberculosis via TLR2‐ROS signalling , 2008, Cellular microbiology.

[11]  F. Di Virgilio,et al.  The P2X7 receptor: a key player in IL-1 processing and release , 2007, The Journal of Immunology.

[12]  J. Tschopp,et al.  The inflammasome: a danger sensing complex triggering innate immunity. , 2007, Current opinion in immunology.

[13]  M. Lotze,et al.  Inside, outside, upside down: damage-associated molecular-pattern molecules (DAMPs) and redox. , 2007, Trends in immunology.

[14]  Cuk-Seong Kim,et al.  Roles of peroxiredoxin II in the regulation of proinflammatory responses to LPS and protection against endotoxin-induced lethal shock , 2007, The Journal of experimental medicine.

[15]  H. Forman,et al.  ATP Activates a Reactive Oxygen Species-dependent Oxidative Stress Response and Secretion of Proinflammatory Cytokines in Macrophages* , 2007, Journal of Biological Chemistry.

[16]  Yoichiro Iwakura,et al.  Interleukin-1beta-driven inflammation promotes the development and invasiveness of chemical carcinogen-induced tumors. , 2007, Cancer research.

[17]  A. I. Rojo,et al.  Glycogen Synthase Kinase-3β Inhibits the Xenobiotic and Antioxidant Cell Response by Direct Phosphorylation and Nuclear Exclusion of the Transcription Factor Nrf2* , 2006, Journal of Biological Chemistry.

[18]  R. Issels,et al.  The cystine/cysteine cycle: a redox cycle regulating susceptibility versus resistance to cell death , 2006, Oncogene.

[19]  F. Martinon,et al.  Gout-associated uric acid crystals activate the NALP3 inflammasome , 2006, Nature.

[20]  H. Park,et al.  Cutting Edge: Direct Interaction of TLR4 with NAD(P)H Oxidase 4 Isozyme Is Essential for Lipopolysaccharide-Induced Production of Reactive Oxygen Species and Activation of NF-κB1 , 2004, The Journal of Immunology.

[21]  M. Torrisi,et al.  Phospholipases C and A2 control lysosome-mediated IL-1 beta secretion: Implications for inflammatory processes. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[22]  G. Filomeni,et al.  Antigen-presenting dendritic cells provide the reducing extracellular microenvironment required for T lymphocyte activation , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[23]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[24]  Freya Q. Schafer,et al.  Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. , 2001, Free radical biology & medicine.

[25]  C. Gabel,et al.  ATP Acts as an Agonist to Promote Stimulus-Induced Secretion of IL-1β and IL-18 in Human Blood , 2000, The Journal of Immunology.

[26]  David S. McClintock,et al.  Role of Oxidants in NF-κB Activation and TNF-α Gene Transcription Induced by Hypoxia and Endotoxin1 , 2000, The Journal of Immunology.

[27]  M. Torrisi,et al.  The secretory route of the leaderless protein interleukin 1beta involves exocytosis of endolysosome-related vesicles. , 1999, Molecular biology of the cell.

[28]  R. Schirmer,et al.  The 58 kDa mouse selenoprotein is a BCNU‐sensitive thioredoxin reductase , 1997, FEBS letters.

[29]  A. Holmgren,et al.  1-Chloro-2,4-dinitrobenzene Is an Irreversible Inhibitor of Human Thioredoxin Reductase , 1995, The Journal of Biological Chemistry.

[30]  P. Ueland,et al.  Determination of the in vivo redox status of cysteine, cysteinylglycine, homocysteine, and glutathione in human plasma. , 1992, Analytical biochemistry.

[31]  F. Cozzolino,et al.  A novel secretory pathway for interleukin‐1 beta, a protein lacking a signal sequence. , 1990, The EMBO journal.

[32]  O. Griffith.  Mechanism of action, metabolism, and toxicity of buthionine sulfoximine and its higher homologs, potent inhibitors of glutathione synthesis. , 1982, The Journal of biological chemistry.

[33]  S. Baek,et al.  Toll-like receptor 9-stimulated monocyte chemoattractant protein-1 is mediated via JNK-cytosolic phospholipase A2-ROS signaling. , 2008, Cellular signalling.

[34]  D. Leibfritz,et al.  Free radicals and antioxidants in normal physiological functions and human disease. , 2007, The international journal of biochemistry & cell biology.

[35]  S. Bannai,et al.  Role of membrane transport in metabolism and function of glutathione in mammals , 2005, The Journal of Membrane Biology.

[36]  光克 宇津木.  Glutathione redox regulates lipopolysaccharide-induced IL-12 production through p38 mitogen-activated protein kinase activation in human monocytes : Role of glutathione redox in IFN-γ priming of IL-12 production , 2003 .

[37]  C. Dinarello,et al.  Interleukin-1, interleukin-1 receptors and interleukin-1 receptor antagonist. , 1998, International reviews of immunology.