Interleukin-6 (IL-6) is a proinflammatory cytokine up-regulated by rhinovirus infection during acute exacerbations of asthma and chronic obstructive pulmonary disease. The role of IL-6 during exacerbations is unclear; however, it is believed IL-6 could contribute to airway and systemic inflammation. In this study we investigate the effects of common asthma treatments fluticasone propionate and β2 agonists salmeterol and salbutamol on IL-6 production in BEAS-2B and primary bronchial epithelial cells. Salmeterol and salbutamol enhanced rhinovirus- and IL-1β-induced IL-6 production; however, fluticasone treatment caused a reduction of IL-6 protein and mRNA. Combined activity of salmeterol and fluticasone at equimolar concentrations had no effect on rhinovirus or IL-1β induction of IL-6. The induction of IL-6 by salmeterol was dependent upon the β2 receptor and could also be induced by cAMP or cAMP-elevating agents forskolin and rolipram. Using transfection of IL-6 promoter reporter constructs, dominant negative mutants, and electromobility shift assays, it was found that NF-κB was the only transcription factor required for rhinovirus induction of IL-6 gene expression. Salmeterol caused an augmentation of rhinovirus-induced promoter activation via a mechanism dependent upon the c/EBP and/or CRE (cyclic AMP response element) cis-acting sites. The suppressive effect of FP was dependent upon distinct glucocorticoid response element sequences proximal to the transcriptional start site within the IL-6 promoter. The data demonstrate that β2 agonists can augment IL-6 expression by other stimuli in an additive manner via cyclic AMP and that the negative effect of steroids is mediated by glucocorticoid response elements within the IL-6 promoter. Interleukin-6 (IL-6) is a proinflammatory cytokine up-regulated by rhinovirus infection during acute exacerbations of asthma and chronic obstructive pulmonary disease. The role of IL-6 during exacerbations is unclear; however, it is believed IL-6 could contribute to airway and systemic inflammation. In this study we investigate the effects of common asthma treatments fluticasone propionate and β2 agonists salmeterol and salbutamol on IL-6 production in BEAS-2B and primary bronchial epithelial cells. Salmeterol and salbutamol enhanced rhinovirus- and IL-1β-induced IL-6 production; however, fluticasone treatment caused a reduction of IL-6 protein and mRNA. Combined activity of salmeterol and fluticasone at equimolar concentrations had no effect on rhinovirus or IL-1β induction of IL-6. The induction of IL-6 by salmeterol was dependent upon the β2 receptor and could also be induced by cAMP or cAMP-elevating agents forskolin and rolipram. Using transfection of IL-6 promoter reporter constructs, dominant negative mutants, and electromobility shift assays, it was found that NF-κB was the only transcription factor required for rhinovirus induction of IL-6 gene expression. Salmeterol caused an augmentation of rhinovirus-induced promoter activation via a mechanism dependent upon the c/EBP and/or CRE (cyclic AMP response element) cis-acting sites. The suppressive effect of FP was dependent upon distinct glucocorticoid response element sequences proximal to the transcriptional start site within the IL-6 promoter. The data demonstrate that β2 agonists can augment IL-6 expression by other stimuli in an additive manner via cyclic AMP and that the negative effect of steroids is mediated by glucocorticoid response elements within the IL-6 promoter. Asthma and chronic obstructive pulmonary disease (COPD) 2The abbreviations used are: COPD, chronic obstructive pulmonary disease; RV, rhinovirus; GC, corticosteroid; LABA, long acting β2 agonist; ASM, airway smooth muscle; c/EBP, CCAAT enhancer-binding protein; CRE, cyclic-AMP response element; GR, glucocortcoid receptor; GRE, glucocorticoid response element; nGRE, negative GRE; SM, salmeterol; FP, fluticasone propionate; IKK, IκB kinase; SB, salbutamol; DN, dominant negative; CMV, cytomegalovirus; ELISA, enzyme-linked immunosorbent assay; NHBE, normal human bronchial epithelial cells. are inflammatory diseases of the airway. Recent evidence suggests a large proportion of exacerbations of both diseases are precipitated due to viral infections (1Nicholson K.G. Kent J. Ireland D.C. BMJ. 1993; 307: 982-986Crossref PubMed Google Scholar, 2Johnston S.L. Pattemore P.K. Sanderson G. Smith S. Lampe F. Josephs L. Symington P. O'Toole S. Myint S.H. Tyrrell D.A. Holgate S.T. 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Care Med. 2006; 173: 871-876Crossref PubMed Scopus (169) Google Scholar), and the most prominent respiratory virus associated with either disease is human rhinovirus (RV) (8Rakes G.P. Arruda E. Ingram J.M. Hoover G.E. Zambrano J.C. Hayden F.G. Platts-Mills T.A. Heymann P.W. Am. J. Respir. Crit. Care Med. 1999; 159: 785-790Crossref PubMed Google Scholar, 9Rawlinson W.D. Waliuzzaman Z. Carter I.W. Belessis Y.C. Gilbert K.M. Morton J.R. J. Infect. Dis. 2003; 187: 1314-1318Crossref PubMed Scopus (142) Google Scholar, 10Seemungal T.A. Harper-Owen R. Bhowmik A. Jeffries D.J. Wedzicha J.A. Eur. Respir. J. 2000; 16: 677-683Crossref PubMed Scopus (255) Google Scholar). Rhinovirus infects the bronchial epithelium and induces a variety of proinflammatory cytokines, chemokines, and adhesion molecules, serving to attract inflammatory cells and prolong local inflammation within the airway (11Fleming H.E. Little F.F. Schnurr D. Avila P.C. Wong H. Liu J. Yagi S. Boushey H.A. Am. J. Respir. Crit. 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Although IL-6 has inflammatory, anti-inflammatory, and immunomodulatory properties, its exact role in either disease remains unclear. Adequate treatment of asthma and COPD exacerbations remains an important therapeutic goal. Inhaled corticosteroids (GCs) and long acting β2 agonists (LABAs) are common treatments for asthma and COPD and exacerbations of these diseases, often used in combination. However, these treatments are only partially effective, reducing rates of asthma exacerbations by 40% and less so for COPD (16Pauwels R.A. Lofdahl C.G. Postma D.S. Tattersfield A.E. O'Byrne P. Barnes P.J. Ullman A. N. Engl. J. Med. 1997; 337: 1405-1411Crossref PubMed Scopus (1545) Google Scholar, 17Calverley P. Pauwels R. Vestbo J. Jones P. Pride N. Gulsvik A. Anderson J. Maden C. Lancet. 2003; 361: 449-456Abstract Full Text Full Text PDF PubMed Scopus (1114) Google Scholar). A thorough understanding of the actions and interactions of these treatments at the physiological, cellular, and molecular level is a major research objective, allowing a more careful application of these treatments to appropriate patients. Several studies have demonstrated the anti-inflammatory potential of GCs; however, their mode of action has been vigorously debated (18Pelaia G. Vatrella A. Cuda G. Maselli R. Marsico S.A. Life Sci. 2003; 72: 1549-1561Crossref PubMed Scopus (94) Google Scholar). Recent evidence also demonstrates that LABAs can enhance the anti-inflammatory action of steroids (19Korn S.H. Jerre A. Brattsand R. Eur. Respir. J. 2001; 17: 1070-1077Crossref PubMed Scopus (113) Google Scholar, 20Pang L. Knox A.J. Am. J. Respir. Cell Mol. Biol. 2000; 23: 79-85Crossref PubMed Google Scholar, 21Pang L. Knox A.J. FASEB J. 2001; 15: 261-269Crossref PubMed Scopus (143) Google Scholar, 22Edwards M.R. Johnson M.W. Johnston S.L. Am. J. Respir. Cell Mol. Biol. 2006; 34: 616-624Crossref PubMed Scopus (96) Google Scholar). LABAs, however, can affect the expression of other genes via cAMP-dependent pathways, such as the induction of IL-6 in airway smooth muscle cells (ASM) (23Ammit A.J. Lazaar A.L. Irani C. O'Neill G.M. Gordon N.D. Amrani Y. Penn R.B. Panettieri Jr., R.A. Am. J. Respir. Cell Mol. Biol. 2002; 26: 465-474Crossref PubMed Google Scholar). The human IL-6 promoter contains several cis-acting proximal to the CCAAT enhancer-binding protein and a cyclic AMP response element and have been in IL-6 transcription a of stimuli (23Ammit A.J. Lazaar A.L. Irani C. O'Neill G.M. Gordon N.D. Amrani Y. Penn R.B. Panettieri Jr., R.A. Am. J. Respir. Cell Mol. Biol. 2002; 26: 465-474Crossref PubMed Google Scholar, A. R. M. M. P. M. J. Biol. 1999; Full Text Full Text PDF PubMed Scopus (169) Google Scholar, Z. A. Y. Jr., J. J.A. J. Clin. PubMed Google Scholar). bronchial epithelial cells both glucocortcoid and β2 and are cells for and β2 in we have the of and IL-1β-induced IL-6 by with salmeterol and fluticasone propionate in primary bronchial epithelial cells and induced IL-6 via IκB and NF-κB and was via by CRE and c/EBP transcription in a cAMP-dependent FP IL-6 via negative glucocorticoid response elements proximal to the IL-6 as of genes that is via a negative in induced IL-6 and protein that the effect of the the data demonstrate that β2 have effects other gene transcription in with and cells the of Cell in with with with and at in a and a and in cells and on cells to S.L. Pattemore P.K. Sanderson G. Smith S. Lampe F. Josephs L. Symington P. O'Toole S. Myint S.H. Tyrrell D.A. Holgate S.T. BMJ. 1995; 310: 1225-1229Crossref PubMed Google Scholar). was and was The of was by on cells and was as A. Johnston S.L. J. Biol. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, S.L. A. P.J. M.M. J. Immunol. 1998; 160: PubMed Google Scholar), and virus was by a at in a for and human IL-1β was in at and at and in at a of and at and FP also in at was also and at in in with at the required IL-6 of or of the IL-6 promoter to A. R. M. M. P. M. J. Biol. 1999; Full Text Full Text PDF PubMed Scopus (169) Google Scholar). IL-6 a and and are and in IL-6 was the and to Mol. 1999; PubMed Scopus Google Scholar, K. E. S. G. J. Biol. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). by A dominant negative of IκB of the promoter was and a by the promoter in and was a and at at of BEAS-2B at cells in with in and to for in with with with of of either of a IL-6 and of also with of the IL-6 reporter and or either a of IκB or and of of of to the on the cells for with of and of with and the cells at in infection for and with or FP or infection with at and IL-1β of the induction and study of BEAS-2B cells and in at in and and to for BEAS-2B cells in infection with SM, SB, and FP at in infection or with for for the of with of or of or IL-1β for with at and IL-1β and with of infection and for was in infection and on the cells for treatment with and or infection with at for induction of promoter BEAS-2B cells as and in infection for with and FP at the required concentrations or for and with of or for with at infection and or FP was on the cells and for to expression of the reporter for for the of IL-6 by and to the of in and with a allowing of The of the was for the of protein activity was and a for to expression a at in a data by at and was and was used for was and for IL-6 and of of and and and (IL-6) or concentrations of and of was to with at for for and of for and for IL-6 expression was to and as of IL-6 of a on with and cells in and as for reporter and protein SM, FP, or and with for with and protein at and protein protein with shift was a to the on the NF-κB site within the human IL-6 promoter with NF-κB also with in data at a with or a as Rhinovirus and IL-1β IL-6 in in have used and and the proinflammatory cytokine IL-1β as of proinflammatory agents that can to IL-6 production in bronchial epithelial cells. major and IL-6 in BEAS-2B cells of A and The induction of IL-6 was due to virus and infection other of the as and virus IL-6 production that IL-1β induces IL-6 of in a of Rhinovirus and IL-1β IL-6 by β2 and in BEAS-2B and FP and β2 agonists and used to investigate or asthma at and IL-1β-induced IL-6 demonstrates the of treatment to affect and IL-6 protein production FP both and IL-6 in a manner In and IL-6 production at and and IL-6 production affect the level of IL-6 production in only with In primary FP IL-6 protein in a manner IL-6 protein in a manner BEAS-2B cells with of and FP at or and IL-1β-induced IL-6, FP to of IL-6 with the used in the of and FP and had affect with or IL-1β the FP was to FP had affect on virus and IL-1β-induced IL-6 used in with at the effects of the of the and in IL-6 IL-1β and with cells with IL-6 and FP reducing IL-6 and in IL-6 with cells of IL-6 protein by or FP and in IL-6 in BEAS-2B with with in a of IL-6 protein by or FP and in IL-6 in cells with FP and at in a and IL-6 with in BEAS-2B cells to investigate the transcriptional induction of IL-6 in BEAS-2B cells. induced IL-6 at with cells at In induced IL-6 and at of IL-6 and induction of IL-6 was the in a manner cAMP IL-6 and also induced IL-6, at with and with the forskolin also induced IL-6 in a manner the also induced IL-6 in BEAS-2B cells and cAMP also induced IL-6 at and in BEAS-2B cells with cells with of IL-6 by cAMP or of IL-6 of in a of NF-κB in data the transcription factor NF-κB in proinflammatory cytokine gene expression Z. 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Lazaar A.L. Irani C. O'Neill G.M. Gordon N.D. Amrani Y. Penn R.B. Panettieri Jr., R.A. Am. J. Respir. Cell Mol. Biol. 2002; 26: 465-474Crossref PubMed Google Scholar, A. R. M. M. P. M. J. Biol. 1999; Full Text Full Text PDF PubMed Scopus (169) Google the human IL-6 promoter is an of a human gene to human disease. data and Z. A. Y. Jr., J. J.A. J. Clin. PubMed Google Scholar, J. D. J. Immunol. 2000; PubMed Google that NF-κB for IL-6 promoter and we have that or is required in BEAS-2B cells. The NF-κB or of transcription are in the of more genes M. Y. PubMed Google Scholar). of NF-κB via and of its via several its NF-κB to the and to within of The activation of NF-κB by is J. D. J. Immunol. 2000; PubMed Google Scholar, J.A. A. J. L. J. PubMed Scopus Google Scholar, M.R. Johnston S.L. J. 2006; PubMed Scopus Google Scholar), and NF-κB has also been in the transcriptional of many genes induced by A. Johnston S.L. J. Biol. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, Z. 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A site of the at was that the proximal site was in of IL-6. element at this could by the and by activity at the transcription start site via or by of transcription with their or of the IL-6 are required to the of this with the and IL-6 are used in with LABAs, we in the effects of on IL-6 and in with found that and to a and cAMP-elevating agents to be of IL-6 protein and mRNA. was due to a response of bronchial epithelial cells to or other in the had no effect on and or on activation normal and and in with FP, the these genes to FP treatment both in BEAS-2B cells and primary bronchial epithelial cells M.R. Johnson M.W. Johnston S.L. Am. J. Respir. Cell Mol. Biol. 2006; 34: 616-624Crossref PubMed Scopus (96) Google Scholar). In the induced IL-6 in both bronchial epithelial and primary bronchial epithelial this was a of the BEAS-2B The effect of on IL-6 induction careful of the IL-6 promoter and also of the on IL-6 induction airway smooth studies have the effects of β2 agonists on IL-6 in and also these agents to be of IL-6 (23Ammit A.J. Lazaar A.L. Irani C. O'Neill G.M. Gordon N.D. Amrani Y. Penn R.B. Panettieri Jr., R.A. Am. J. Respir. Cell Mol. Biol. 2002; 26: 465-474Crossref PubMed Google Scholar). can be by the IL-6 is to a CRE element of that in cells (23Ammit A.J. Lazaar A.L. Irani C. O'Neill G.M. Gordon N.D. Amrani Y. Penn R.B. Panettieri Jr., R.A. Am. J. Respir. Cell Mol. Biol. 2002; 26: 465-474Crossref PubMed Google Scholar). The IL-6 promoter also contains a c/EBP or site to that also to M. Johnson Anderson G. M. J.L. 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Biol. PubMed Google Scholar). In CRE and c/EBP have been found in in a of genes J. K. W.R. Mol. Biol. PubMed Google Scholar, S.A. N. S.A. Mol. 2002; PubMed Scopus Google Scholar, R. S. A. I. Johnson J. Biol. 2006; Full Text Full Text PDF PubMed Scopus Google and can in to gene the of these sequences is often studies are required to the transcription that mediated cAMP induction of IL-6 and these transcription with CRE or c/EBP cAMP and cAMP-elevating agents an and a induced IL-6 protein and in BEAS-2B the data to a that transcriptional activation of the IL-6 β2 agonists via and this to activation of several pathways, protein A. we study the to IL-6 gene it is protein A or is for c/EBP or CRE transcription protein A can both and c/EBP R. S. A. I. Johnson J. Biol. 2006; Full Text Full Text PDF PubMed Scopus Google transcription the role of protein A in IL-6 LABAs are and their in asthma and COPD is of this In with β2 agonists also anti-inflammatory and and in evidence suggests are of this used (19Korn S.H. Jerre A. Brattsand R. Eur. Respir. J. 2001; 17: 1070-1077Crossref PubMed Scopus (113) Google Scholar, 21Pang L. Knox A.J. FASEB J. 2001; 15: 261-269Crossref PubMed Scopus (143) Google Scholar, 22Edwards M.R. Johnson M.W. Johnston S.L. Am. J. Respir. Cell Mol. Biol. 2006; 34: 616-624Crossref PubMed Scopus (96) Google Scholar, M. Johnson Anderson G. M. J.L. Lancet. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). is more to be the and of β2 this study and have demonstrated that genes be up-regulated by β2 the of β2 agonists in it is that of the effect be due to the of as CRE genes as as the anti-inflammatory and studies are required to investigate genes in asthma and COPD are by β2 IL-6 a or role in the of disease remains IL-6 is as a proinflammatory cytokine, the of is in the of many inflammatory is evidence to that IL-6 to the of and inflammatory diseases, such as disease. IL-6 are to D. S. PubMed Scopus Google Scholar). IL-6 also with the of disease T. H.E. J. Clin. 1995; PubMed Google Scholar). The role of IL-6 in respiratory diseases, however, is so IL-6 a role in and pulmonary inflammation is in airway R.A. L. S.A. Am. J. 2005; PubMed Scopus Google Scholar). IL-6 had no effect on C. R.J. Z. N. R.A. G.P. J.A. Am. J. Respir. Cell Mol. Biol. 2000; PubMed Google Scholar). in the IL-6 have an anti-inflammatory role as in IL-6 have of proinflammatory cytokines and inflammatory Z. J. G. H. M. J. Clin. 1998; PubMed Google and inflammatory cells to an Z. M. K. S. N. Clin. 34: PubMed Scopus Google Scholar). The data that IL-6 have inflammatory in this affect airway in the data evidence that steroids and β2 agonists be as as steroids potential proinflammatory genes by β2 In and β2 agonists have effects on IL-6 transcription in bronchial epithelial cells. IL-1β and IL-6 via a mechanism an element proximal to the In β2 agonists and cAMP agents IL-6 and augment and IL-1β-induced IL-6 via c/EBP and/or CRE within the IL-6 promoter. The data that proinflammatory genes are in the manner by and β2 agonists and that an understanding of the transcriptional of proinflammatory genes can in understanding these common asthma treatments affect their expression.
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