Oxidant Tone Regulates RANTES Gene Expression in Airway Epithelial Cells Infected with Respiratory Syncytial Virus

Abstract

Respiratory syncytial virus (RSV) produces intense pulmonary inflammation, in part, through its ability to induce chemokine synthesis in infected airway epithelial cells. RANTES (regulated upon activation, normal T-cells expressed and secreted) is a CC chemokine which recruits and activates monocytes, lymphocytes, and eosinophils, all cell types present in the lung inflammatory infiltrate induced by RSV infection. In this study we investigated the role of reactive oxygen species in the induction of RANTES gene expression in human type II alveolar epithelial cells (A549), following RSV infection. Our results indicate that RSV infection of airway epithelial cells rapidly induces reactive oxygen species production, prior to RANTES expression, as measured by oxidation of 2′,7′-dichlorofluorescein. Pretreatment of airway epithelial cells with the antioxidant butylated hydroxyanisol (BHA), as well a panel of chemically unrelated antioxidants, blocks RSV-induced RANTES gene expression and protein secretion. This effect is mediated through the ability of BHA to inhibit RSV-induced interferon regulatory factor binding to the RANTES promoter interferon-stimulated responsive element, that is absolutely required for inducible RANTES promoter activation. BHA inhibits de novo interferon regulator factor (IRF)-1 and -7 gene expression and protein synthesis, and IRF-3 nuclear translocation. Together, these data indicates that a redox-sensitive pathway is involved in RSV-induced IRF activation, an event necessary for RANTES gene expression. Respiratory syncytial virus (RSV) produces intense pulmonary inflammation, in part, through its ability to induce chemokine synthesis in infected airway epithelial cells. RANTES (regulated upon activation, normal T-cells expressed and secreted) is a CC chemokine which recruits and activates monocytes, lymphocytes, and eosinophils, all cell types present in the lung inflammatory infiltrate induced by RSV infection. In this study we investigated the role of reactive oxygen species in the induction of RANTES gene expression in human type II alveolar epithelial cells (A549), following RSV infection. Our results indicate that RSV infection of airway epithelial cells rapidly induces reactive oxygen species production, prior to RANTES expression, as measured by oxidation of 2′,7′-dichlorofluorescein. Pretreatment of airway epithelial cells with the antioxidant butylated hydroxyanisol (BHA), as well a panel of chemically unrelated antioxidants, blocks RSV-induced RANTES gene expression and protein secretion. This effect is mediated through the ability of BHA to inhibit RSV-induced interferon regulatory factor binding to the RANTES promoter interferon-stimulated responsive element, that is absolutely required for inducible RANTES promoter activation. BHA inhibits de novo interferon regulator factor (IRF)-1 and -7 gene expression and protein synthesis, and IRF-3 nuclear translocation. Together, these data indicates that a redox-sensitive pathway is involved in RSV-induced IRF activation, an event necessary for RANTES gene expression. respiratory syncytial virus regulated upon activation, normal T-cells expressed and secreted reactive oxygen species N-acetylcystein tetramethyl thiourea butylated hydroxyanisol interferon-stimulated responsive element interferon regulatory factor extracellular signal-regulated kinase mitogen-activated protein human immunodeficiency virus interleukin small alveolar epithelial cells multiplicity of infection 2,7-dichlorofluorescein diacetate polyacrylamide gel electrophoresis signal transducers and activators of transcription Respiratory syncytial virus (RSV)1 is an enveloped, negative-sense single-stranded RNA virus (1Hall C.B. McCarthy C.A. Mandel G.L. Bennett J.E. Dolin R. Principles and Practice of Infectious Diseases. Churchill Livingston, New York1995Google Scholar). Since its isolation, RSV has been identified as a leading cause of epidemic respiratory tract illness in children in the United States and worldwide. In fact, RSV is so ubiquitous that it will infect 100% of children before the age of 3. It is estimated that 40–50% of children hospitalized with bronchiolitis and 25% of children with pneumonia are infected with RSV, resulting in 100,000 hospital admissions annually in the United States alone (1Hall C.B. McCarthy C.A. Mandel G.L. Bennett J.E. Dolin R. Principles and Practice of Infectious Diseases. Churchill Livingston, New York1995Google Scholar). In addition to acute morbidity, there are long-term consequences of RSV infection in infancy: RSV has been shown to predispose to the development of hyperreactive airway disease (2Webb M.S.C. Henry R.L. Milner A.D. Arch. Dis. Child. 1985; 60: 1064-1067Crossref PubMed Scopus (63) Google Scholar) and recurrent episodes of wheezing in asthmatic children are often precipitated by RSV infection. The mechanisms of RSV-induced airway disease and its long-term consequences are largely unknown, but the delicate balance between immunopathology and immunoprotection in the airway mucosa may be altered by an exuberant and unwanted local inflammatory response. Airway infiltration of monocytes and lymphocytes is typical of RSV infection (1Hall C.B. McCarthy C.A. Mandel G.L. Bennett J.E. Dolin R. Principles and Practice of Infectious Diseases. Churchill Livingston, New York1995Google Scholar), and activation of eosinophil and basophil leukocytes has been shown to correlate with the severity of acute RSV disease (3Garofalo R.P. Welliver R.C. Ogra P.L. Pediatr. Allergy Immunol. 1991; 2: 30-37Crossref Scopus (26) Google Scholar, 4Garofalo R.P. Kimpen J.L.L. Welliver R.C. Ogra P.L. J. Pediatrics. 1992; 120: 28-32Abstract Full Text PDF PubMed Scopus (265) Google Scholar). The composition of the cellular response at sites of tissue inflammation is controlled by gradients of chemokines, a family of small chemotactic cytokines, which direct leukocyte transendothelial migration and movement through the extracellular matrix. RANTES is a CC chemokine highly chemoattractant for T lymphocytes, monocytes, eosinophils, and basophils (5Alam R. Stafford S. Forsythe P. Harrison R. Faubion D. Lett-Brown M.A. Grant J.A. J. Immunol. 1993; 150: 3442-3448PubMed Google Scholar), all cell types which are present or activated in the inflammatory infiltrate that follows RSV infection of the lung. Recent in vivo studies have shown elevated RANTES concentrations in nasal washes and bronchoalveolar lavages of children infected with RSV (6Teran L.M. Seminario M.C. Shute J.K. Papi A. Compton S.J. Low J.L. Gleich G.J. Johnston S.L. J. Infect. Dis. 1999; 179: 677-681Crossref PubMed Scopus (77) Google Scholar, 7Sheeran P. Jafri H. Carubelli C. Saavedra J. Johnson C. Krisher K. Sanchez P.J. Ramilio M.O. Pediatr. Infect. Dis. J. 1999; 18: 115-122Crossref PubMed Scopus (223) Google Scholar) and we have recently shown that RANTES is strongly expressed in RSV-infected respiratory epithelial cells (8Saito T. Deskin R.W. Casola A. Haeberle H. Olszewska B. Ernst P.B. Alam R. Ogra P.L. Garofalo R. J. Infect. Dis. 1997; 175: 497-504Crossref PubMed Scopus (149) Google Scholar, 9Olszewska-Pazdrak B. Casola A. Saito T. Alam R. Crowe S.E. Mei F. Ogra P.L. Garofalo R.P. J. Virol. 1998; 72: 4756-4764Crossref PubMed Google Scholar), which are the primary target for viral infection. Therefore, it is likely that RANTES produced by infected epithelial cells plays an important role in the pathogenesis of RSV-induced airway inflammation. Reactive oxygen species (ROS) are ubiquitous, highly diffusable and reactive molecules produced as a result of reduction of molecular oxygen, including species such as hydrogen peroxide, superoxide anion, and hydroxyl radical, and they have been implicated in damaging cellular components like lipids, proteins, and DNA. In the past few years, there has been increased recognition of their role as redox regulators of cellular signaling (reviewed in Refs. 10Allen R.G. Tresini M. Free Radic. Biol. Med. 2000; 28: 463-499Crossref PubMed Scopus (1073) Google Scholar and 11Prasad Gabbita S. Robinson K.A. Stewart C.A. Floyd R.A. Hensley K. Arch. Biochem. Biophys. 2000; 376: 1-136Crossref PubMed Scopus (155) Google Scholar). Inducible ROS generation has been shown following stimulation with a variety of molecules, like cytokines and growth factors, and infection with certain viruses, like HIV, hepatitis B, and influenza (reviewed in Ref. 12Schwarz K.B. Free Radic. Biol. Med. 1996; 21: 641-649Crossref PubMed Scopus (541) Google Scholar). Changes in the level of ROS, generated in response to some of these stimuli, have been shown to modulate the expression of several genes (10Allen R.G. Tresini M. Free Radic. Biol. Med. 2000; 28: 463-499Crossref PubMed Scopus (1073) Google Scholar). Among the different members of the chemokine family, interleukin (IL)-8 is the only one for which redox-sensitive signaling pathways have been identified (13Simeonova P.P. Leonard S. Flood L. Shi X. Luster M.I. Lab. 1999; Google Scholar, J. J. Biol. 1993; Full Text PDF PubMed Google Scholar). The of ROS in RANTES gene expression, as well as in CC chemokine has been Therefore, the of this study to the effect of RSV infection ROS generation in human airway epithelial cells and the role of ROS in RSV-induced RANTES Our results indicate that RSV infection of airway epithelial cells induces ROS production, as measured by oxidation of and that of airway epithelial cells with the antioxidant butylated hydroxyanisol (BHA), as well as a panel of chemically unrelated antioxidants, blocks RSV-induced RANTES protein and gene expression. This effect is mediated through the of RSV-induced interferon regulatory factor binding to the RANTES interferon-stimulated responsive element an event that is absolutely required for RANTES gene In infected and and -7 are inducible upon RSV infection of alveolar epithelial cells and with BHA inhibits their gene expression and protein In IRF-3 is expressed and antioxidant blocks its nuclear translocation. data strongly indicate that a redox-sensitive pathway is involved in RSV-induced IRF induction and RANTES gene expression. This study the role of ROS in RANTES and IRF protein activation. of the molecular mechanisms involved in RANTES gene expression is for to modulate the inflammatory response with RSV infection of the lung. The human of RSV in cells and by gradients as Med. Google Scholar). The virus of the RSV a cytokines in these viral J.A. M. Garofalo R. T. S. T. Ogra P.L. F. J. PubMed Scopus Google Scholar). the and at human alveolar type epithelial cells in and alveolar epithelial cells and to the infected with RSV at a multiplicity of infection of as R.P. M. Casola A. Ogra P.L. J. Virol. 1996; PubMed Google Scholar). of a to as a the antioxidant cells with the for and infected in the of the Since BHA in of to as a of cell and viral following antioxidant measured by and by RANTES by a following the RNA and infected cells by the J.E. J. 1991; PubMed Scopus Google Scholar). of RNA a to and to a and -7 a of A. and -7 a of for as M. Casola A. Garofalo R.P. J. Biol. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). for all for at and with a cells in tissue and infected with RSV at and multiplicity of infection different cells with and with 2,7-dichlorofluorescein diacetate in for at The cells and at and an the in which as a for ROS production, cells with for and measured at different following addition of in and results expressed as of of the human RANTES promoter to to the the gene and as of the RANTES in the of by the following and in and cells in in by as A. Garofalo R.P. M. S. J. Immunol. 2000; PubMed Scopus Google Scholar). in of of with of and of and of in to the cells for with and in The cells infected with RSV and at cells to and as A. Garofalo R.P. M. S. J. Immunol. 2000; PubMed Scopus Google Scholar). to the in or of and infected cells as A. Garofalo R.P. M. S. J. Immunol. 2000; PubMed Scopus Google Scholar). by protein and to to a to the RANTES is of nuclear proteins, of and in a of The nuclear with the for at and by polyacrylamide in and for at of binding to the RANTES a A. Garofalo R.P. M. S. J. Immunol. 2000; PubMed Scopus Google Scholar). In this are chemically a The of infected cells nuclear at for with of in the or of of type or The binding of and of a of to the and at for an with with of binding and the in of and a electrophoresis to for cell and and nuclear as by and to A. Garofalo R.P. M. S. J. Immunol. 2000; PubMed Scopus Google Scholar). with in and with a to and -7 we a or in the to by the for different at a RSV infection induced ROS production, cells to of and infected with different cells with the which is following by cellular oxidation measured by in in infected cells J.A. H. Free Radic. 1997; PubMed Scopus Google C. R.P. Free Radic. Biol. Med. 1999; PubMed Scopus Google Scholar). cells infected with of the of ROS as as a and the level of cellular ROS in infected cells in cells at cells infected with a multiplicity of such as and the of ROS of a few a between and the of cells infected at the have recently that RSV is a for RANTES in human and alveolar epithelial cells (8Saito T. Deskin R.W. Casola A. Haeberle H. Olszewska B. Ernst P.B. Alam R. Ogra P.L. Garofalo R. J. Infect. Dis. 1997; 175: 497-504Crossref PubMed Scopus (149) Google Scholar, 9Olszewska-Pazdrak B. Casola A. Saito T. Alam R. Crowe S.E. Mei F. Ogra P.L. Garofalo R.P. J. Virol. 1998; 72: 4756-4764Crossref PubMed Google Scholar). In all epithelial cell synthesis of RANTES required virus and and with increased of RANTES between and infection (8Saito T. Deskin R.W. Casola A. Haeberle H. Olszewska B. Ernst P.B. Alam R. Ogra P.L. Garofalo R. J. Infect. Dis. 1997; 175: 497-504Crossref PubMed Scopus (149) Google B. Casola A. Saito T. Alam R. Crowe S.E. Mei F. Ogra P.L. Garofalo R.P. J. Virol. 1998; 72: 4756-4764Crossref PubMed Google Scholar). the of RSV-induced ROS generation in RANTES cells infected with RSV in the or of the chemically unrelated tetramethyl thiourea and butylated hydroxyanisol In studies different concentrations of to the in RANTES that and BHA to RSV-induced RANTES production, with BHA the these results in a normal cell in cells infected with cells are the small of the lung and they a of RANTES following RSV with cells B. Casola A. Saito T. Alam R. Crowe S.E. Mei F. Ogra P.L. Garofalo R.P. J. Virol. 1998; 72: 4756-4764Crossref PubMed Google Scholar). in the and BHA RSV-induced RANTES that inducible RANTES is regulated in a redox-sensitive cell or viral Since BHA the in RSV-induced RANTES in and we this antioxidant to all the the ability of BHA to inhibit ROS, cells with in the or of BHA and the of cellular ROS by oxidation of shown in to induce a level of ROS production, which by with data indicate that BHA as a antioxidant in airway epithelial cells. the reduction in RSV-induced RANTES by BHA by in the level of RANTES cells infected with RSV for of in the or of the and RNA and infected cells for small in RANTES expression at with induction between and in at with BHA RSV-induced RANTES induction at and and it at This to a effect cell and in the with antioxidant and of the gene with cells Inducible RANTES gene expression is controlled at and T. M. S. A. 1999; PubMed Scopus Google Scholar, P.J. J. Immunol. 1993; Google Scholar, S. S. A. T. D. P.J. J. Immunol. 2000; PubMed Scopus Google Scholar). have shown that in cells RSV-induced RANTES promoter activation the induction of the RANTES gene that in alveolar epithelial cells RANTES expression, following RSV is controlled at the level of R. P. H. T. F. M. and A. R. Virol. the antioxidant effect of BHA RANTES gene cells with a the of the human RANTES promoter to the as This of the promoter all the necessary regulatory that regulated expression in cells following RSV The cells infected with RSV for in the or of to we have for with BHA RSV-induced that the antioxidant effect by with RANTES gene have recently investigated the and nuclear involved in the of RANTES gene transcription following RSV infection of human airway epithelial cells. The results of that study have that RSV-induced RANTES transcription of response including the The is absolutely required for RSV-induced promoter activation, its blocks RSV-induced of RANTES transcription to in the of the RANTES we nuclear cells or infected with RSV for in the or of shown in RSV infection induced a in which by with of RANTES binding in response to antioxidant and cells infected with RSV for in the or of and for binding to the RANTES in is the the RANTES in response to RSV The components of the RSV-induced binding are and It has been shown that gene expression and protein synthesis is viral IRF-3 is expressed and to the in response to a viral infection J. P. P. H. C. M. R. J. 1999; PubMed Scopus Google Scholar). have shown that RSV infection of cells induces de novo synthesis of A. Garofalo R.P. M. S. J. Immunol. 2000; PubMed Scopus Google Scholar). RSV infection of cells induced synthesis and IRF-3 activation, we of and nuclear cells or infected for of shown in RSV infection novo synthesis of and its nuclear IRF-3 expressed and RSV infection induced its nuclear The of IRF-3 at with likely to the effect of nuclear and of the activated R. C. J. Biol. 1998; 18: PubMed Scopus Google Scholar). of RSV-infected alveolar epithelial cells the nuclear of and -7 and one of the nuclear of as shown in of BHA IRF nuclear in cells infected with cells infected with RSV for and in the or of to nuclear and of protein and infected cells for and -7 by the nuclear of IRF-3 RSV Since the nuclear of IRF-3 by BHA we this to to the RANTES this we a In this to nuclear of and infected cells A. Garofalo R.P. M. S. J. Immunol. 2000; PubMed Scopus Google Scholar). by the addition of and the of IRF-3 by shown in there binding of IRF-3 in nuclear but its increased RSV infection. BHA IRF-3 that the nuclear of IRF-3 by antioxidant is to to and to the RANTES the reduction in nuclear of and -7 following antioxidant to of IRF gene expression, protein synthesis, or nuclear we of cell and RSV-infected in the or of RSV infection induced a of and -7 protein expression and it a in the of one of the of an event likely to in IRF-3 as it has been in cells B. C. L. S. R. J. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). BHA RSV-induced and -7 protein synthesis and IRF-3 Since the of and -7 protein present in the cell is their gene expression, we of and -7 following RSV infection in the or of and -7 by antioxidant at and and at the IRF-3 level increased following RSV infection and by the antioxidant In these results strongly that a redox-sensitive signaling pathway is involved in IRF activation and RANTES gene expression following RSV infection of alveolar epithelial cells. normal airway epithelial cells an important between the and the infection or they an important role in the response by factors, like chemokines, a family of small chemotactic cytokines, which are to and leukocytes in a Immunol. 1992; Google Scholar). The of the airway is of to RSV the inflammatory response by RSV infection to be an of RSV-induced lung T. J. J. PubMed Scopus Google Scholar). RANTES is a CC chemokine highly chemoattractant for T lymphocytes, monocytes, eosinophils, and all cell types which are present or activated in the inflammatory infiltrate that follows RSV infection of the lung. RANTES concentrations are elevated in nasal washes and bronchoalveolar lavages of children infected with RSV (6Teran L.M. Seminario M.C. Shute J.K. Papi A. Compton S.J. Low J.L. Gleich G.J. Johnston S.L. J. Infect. Dis. 1999; 179: 677-681Crossref PubMed Scopus (77) Google Scholar, 7Sheeran P. Jafri H. Carubelli C. Saavedra J. Johnson C. Krisher K. Sanchez P.J. Ramilio M.O. Pediatr. Infect. Dis. J. 1999; 18: 115-122Crossref PubMed Scopus (223) Google Scholar) and RANTES gene is strongly expressed in RSV-infected respiratory epithelial cells (8Saito T. Deskin R.W. Casola A. Haeberle H. Olszewska B. Ernst P.B. Alam R. Ogra P.L. Garofalo R. J. Infect. Dis. 1997; 175: 497-504Crossref PubMed Scopus (149) Google Scholar, 9Olszewska-Pazdrak B. Casola A. Saito T. Alam R. Crowe S.E. Mei F. Ogra P.L. Garofalo R.P. J. Virol. 1998; 72: 4756-4764Crossref PubMed Google Scholar), that its by infected epithelial cells may an important role in the pathogenesis of RSV-induced airway inflammation. Free and reactive oxygen species have recently been shown to as a variety of molecular and including expression of a of genes (reviewed in Ref. 10Allen R.G. Tresini M. Free Radic. Biol. Med. 2000; 28: 463-499Crossref PubMed Scopus (1073) Google Scholar). The results of this study that RSV infection of alveolar epithelial cells induces ROS and activates a redox-sensitive signaling pathway leading to de novo synthesis of the transcription and -7 and nuclear of IRF-3 that a role in RANTES gene R. C. P. J. Biol. 1999; PubMed Scopus Google Scholar). This is the of increased ROS in airway epithelial cells following RSV infection. Our data that the of ROS generation in infected cells is and RSV-induced transcription factor activation and in RANTES studies have to the ability of certain viruses, including hepatitis B, and HIV, to induce the of ROS (reviewed in Ref. 12Schwarz K.B. Free Radic. Biol. Med. 1996; 21: 641-649Crossref PubMed Scopus (541) Google Scholar). In the ROS generation a of the activation of like monocytes and to we have shown for eosinophils, in which RSV infection induce superoxide J.L. Garofalo R.P. Welliver R.C. Ogra P.L. Pediatr. 1992; PubMed Scopus (63) Google Scholar). The between ROS and molecular and in infected cells has been investigated only for ROS generation has been to gene expression and K.B. Free Radic. Biol. Med. 1996; 21: 641-649Crossref PubMed Scopus (541) Google Scholar), a role for ROS has recently been in transcription factor activation and gene expression M. C. C. R. S. J. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). RSV infection of epithelial cells induce ROS by a study by J. Biol. PubMed Scopus Google Scholar), that antioxidant of infected cells to protein synthesis and induction of a chemokine that has been investigated in the past few years, activation signaling pathways (13Simeonova P.P. Leonard S. Flood L. Shi X. Luster M.I. Lab. 1999; Google Scholar, J. J. Biol. 1993; Full Text PDF PubMed Google Scholar). that study RSV-induced ROS Since the that reactive oxygen species as in signal pathways leading to of gene there has been an in the of genes expression has been to be by cellular redox there only one a role of ROS in RANTES gene expression, antioxidant of cells with which ROS to inhibit RANTES induction J.A. B. B. P. J. 1997; Google Scholar). the of RANTES by the antioxidant In this study we to that of RSV-infected airway epithelial cells with a panel of chemically unrelated inhibit RANTES and the of ROS in RANTES gene expression. in this study we which species of ROS are induced in alveolar epithelial cells infected with RSV, they we to in RSV-induced RANTES in cells with the a result by J. Biol. PubMed Scopus Google Scholar) for RSV-induced secretion. IRF transcription have been shown to a role in the induction of several genes involved in the response to viral including interferon and cytokines like molecules, molecules, and inducible (reviewed in Ref. H. J. 1997; Scopus Google Scholar). RSV has been shown to predispose to the development of (2Webb M.S.C. Henry R.L. Milner A.D. Arch. Dis. Child. 1985; 60: 1064-1067Crossref PubMed Scopus (63) Google Scholar) and recurrent episodes of wheezing in asthmatic children are often precipitated by RSV infection. expression has been recently in airway epithelial cells of with but in normal or with D. M. J. 1999; PubMed Scopus Google Scholar). IRF protein binding to the of RANTES promoter is necessary for viral induction of RANTES transcription and gene R. C. P. J. Biol. 1999; PubMed Scopus Google Scholar). In alveolar epithelial cells and -7 are present in the the following RSV infection and all are involved in RSV-induced RANTES promoter In this we for the that the antioxidant with RSV-induced RANTES transcription by of IRF binding to the its including of IRF gene expression, protein synthesis, or nuclear translocation. and -7 and protein are increased in cells following RSV infection and by the with The of and -7 protein synthesis is likely the for their nuclear in RSV-infected cells with it is that BHA and -7 which is important for their nuclear and binding H. J. 1997; Scopus Google Scholar). gene expression is induced by and cytokines through the activation of and transcription H. S. K. T. Biol. PubMed Scopus Google Scholar). activates gene transcription through an that members of the family R. J. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). BHA of cells RSV-induced nuclear and binding Therefore, it is that BHA RSV-induced activation, leading to of and -7 gene expression. of and nuclear is likely the by which BHA inhibits RSV-induced IRF-3 activation. IRF-3 gene is expressed and IRF-3 protein is present in cells in to different and sites of its as recently by B. C. L. S. R. J. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). have recently shown that IRF-3 as in IRF-3 and II a with as well as disease and viruses, all like RSV, induces the of and which of The are to to the to induce gene expression. In the of we to of IRF-3 in cells. RSV we a which is likely to a II of by antioxidant This to the to RANTES and to the nuclear of IRF-3 which following BHA and is present in the RSV-induced binding as shown by The signaling pathway leading to IRF-3 activation is C. J. Biol. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar) have recently shown that necessary for the in epithelial cells with and that the antioxidant to inhibit induction by with activation. In the of and are as redox-sensitive signaling molecules involved in activation, are important for its gene expression C. J. Biol. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar), be activated by stimulation and are by antioxidant (reviewed in Ref. 1999; 18: PubMed Scopus Google Scholar). this may be the for RSV-induced IRF activation. In fact, we have that is involved in RSV-induced RANTES of activation RSV induced binding to the RANTES result is in with the recently by B. C. L. S. R. J. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar) that of and IRF-3 activation by virus infection. In study indicates that the signaling pathway leading to and -7 protein expression and IRF-3 activation one or redox-sensitive molecules that be different the studies are in to signaling molecules activated by RSV infection and leading to IRF protein induction and activation and RANTES of the molecular mechanisms involved in RSV-induced gene expression is for to modulate the inflammatory response with RSV infection of the lung. for and A. and R. M. for with the oxidation