{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T01:57:18Z","timestamp":1790301438254,"version":"4.1.0"},"reference-count":58,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,9,20]],"date-time":"2017-09-20T00:00:00Z","timestamp":1505865600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,9,20]],"date-time":"2017-09-20T00:00:00Z","timestamp":1505865600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Immune response in the lung has to protect the huge alveolar surface against pathogens while securing the delicate lung structure. Macrophages and alveolar epithelial cells constitute the first line of defense and together orchestrate the initial steps of host defense. In this study, we analysed the influence of macrophages on type II alveolar epithelial cells during<jats:italic>Legionella pneumophila<\/jats:italic>-infection by a systems biology approach combining experimental work and mathematical modelling. We found that<jats:italic>L<\/jats:italic>.<jats:italic>pneumophila<\/jats:italic>-infected THP-1-derived macrophages provoke a pro-inflammatory activation of neighboring lung epithelial cells, but in addition render them hypo-responsive to direct infection with the same pathogen. We generated a kinetic mathematical model of macrophage activation and identified a paracrine mechanism of macrophage-secreted IL-1\u03b2 inducing a prolonged IRAK-1 degradation in lung epithelial cells. This intercellular crosstalk may help to avoid an overwhelming inflammatory response by preventing excessive local secretion of pro-inflammatory cytokines and thereby negatively regulating the recruitment of immune cells to the site of infection. This suggests an important but ambivalent immunomodulatory role of macrophages in lung infection.<\/jats:p>","DOI":"10.1038\/s41598-017-12154-4","type":"journal-article","created":{"date-parts":[[2017,9,14]],"date-time":"2017-09-14T13:50:47Z","timestamp":1505397047000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["THP-1-derived macrophages render lung epithelial cells hypo-responsive to Legionella pneumophila \u2013 a systems biology study"],"prefix":"10.1038","volume":"7","author":[{"given":"Christine","family":"Schulz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Lai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilhelm","family":"Bertrams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Lena","family":"Jung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Sittka-Stark","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina Elena","family":"Herkt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harshavadhan","family":"Janga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katja","family":"Zscheppang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0135-3938","authenticated-orcid":false,"given":"Christina","family":"Stielow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leon","family":"Schulte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Hippenstiel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3076-5122","authenticated-orcid":false,"given":"Julio","family":"Vera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernd","family":"Schmeck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,9,20]]},"reference":[{"key":"12154_CR1","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1001\/jama.281.1.61","volume":"281","author":"GL Armstrong","year":"1999","unstructured":"Armstrong, G. L., Conn, L. A. & Pinner, R. W. Trends in infectious disease mortality in the United States during the 20th century. JAMA 281, 61\u201366 (1999).","journal-title":"JAMA"},{"key":"12154_CR2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.0030076","volume":"3","author":"JP Mizgerd","year":"2006","unstructured":"Mizgerd, J. P. Lung infection\u2013a public health priority. PLoS Med 3, e76, https:\/\/doi.org\/10.1371\/journal.pmed.0030076 (2006).","journal-title":"PLoS Med"},{"key":"12154_CR3","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1136\/thx.2009.129502","volume":"67","author":"T Welte","year":"2012","unstructured":"Welte, T., Torres, A. & Nathwani, D. Clinical and economic burden of community-acquired pneumonia among adults in Europe. Thorax 67, 71\u201379, https:\/\/doi.org\/10.1136\/thx.2009.129502 (2012).","journal-title":"Thorax"},{"key":"12154_CR4","unstructured":"WHO. Pneumonia (2015)."},{"key":"12154_CR5","doi-asserted-by":"crossref","unstructured":"Wardlaw, T., White Johansson, E. & Hodge M. Pneumonia: The forgotten killer of children. (UNICEF\/WHO 2006).","DOI":"10.1016\/S0140-6736(06)69334-3"},{"key":"12154_CR6","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1165\/rcmb.2010-0210OC","volume":"45","author":"LA Pittet","year":"2011","unstructured":"Pittet, L. A. et al. Earliest innate immune responses require macrophage RelA during pneumococcal pneumonia. Am J Respir Cell Mol Biol 45, 573\u2013581, https:\/\/doi.org\/10.1165\/rcmb.2010-0210OC (2011).","journal-title":"Am J Respir Cell Mol Biol"},{"key":"12154_CR7","doi-asserted-by":"publisher","first-page":"6257","DOI":"10.4049\/jimmunol.170.12.6257","volume":"170","author":"ME Poynter","year":"2003","unstructured":"Poynter, M. E., Irvin, C. G. & Janssen-Heininger, Y. M. W. A Prominent Role for Airway Epithelial NF- B Activation in Lipopolysaccharide-Induced Airway Inflammation. J Immunol 170, 6257\u20136265, https:\/\/doi.org\/10.4049\/jimmunol.170.12.6257 (2003).","journal-title":"J Immunol"},{"key":"12154_CR8","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1183\/09031936.00196408","volume":"35","author":"C Hess","year":"2010","unstructured":"Hess, C. et al. Myeloid RelA regulates pulmonary host defense networks. Eur Respir J 35, 343\u2013352, https:\/\/doi.org\/10.1183\/09031936.00196408 (2010).","journal-title":"Eur Respir J"},{"key":"12154_CR9","doi-asserted-by":"publisher","first-page":"1140","DOI":"10.1128\/IAI.05697-11","volume":"80","author":"HM Marriott","year":"2012","unstructured":"Marriott, H. M. et al. Interleukin-1 beta Regulates CXCL8 Release and Influences Disease Outcome in Response to Streptococcus pneumoniae, Defining Intercellular Cooperation between Pulmonary Epithelial Cells and Macrophages. Infect Immun 80, 1140\u20131149, https:\/\/doi.org\/10.1128\/Iai.05697-11 (2012).","journal-title":"Infect Immun"},{"key":"12154_CR10","doi-asserted-by":"publisher","first-page":"7530","DOI":"10.4049\/jimmunol.175.11.7530","volume":"175","author":"MR Jones","year":"2005","unstructured":"Jones, M. R., Simms, B. T., Lupa, M. M., Kogan, M. S. & Mizgerd, J. P. Lung NF-kappaB activation and neutrophil recruitment require IL-1 and TNF receptor signaling during pneumococcal pneumonia. J Immunol 175, 7530\u20137535 (2005).","journal-title":"J Immunol"},{"key":"12154_CR11","doi-asserted-by":"publisher","first-page":"1937","DOI":"10.1084\/jem.20120983","volume":"209","author":"K Steinwede","year":"2012","unstructured":"Steinwede, K. et al. TNF-related apoptosis-inducing ligand (TRAIL) exerts therapeutic efficacy for the treatment of pneumococcal pneumonia in mice. J Exp Med 209, 1937\u20131952, https:\/\/doi.org\/10.1084\/jem.20120983 (2012).","journal-title":"J Exp Med"},{"key":"12154_CR12","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1111\/cei.12170","volume":"174","author":"JD Aberdein","year":"2013","unstructured":"Aberdein, J. D., Cole, J., Bewley, M. A., Marriott, H. M. & Dockrell, D. H. Alveolar macrophages in pulmonary host defence the unrecognized role of apoptosis as a mechanism of intracellular bacterial killing. Clin Exp Immunol 174, 193\u2013202, https:\/\/doi.org\/10.1111\/cei.12170 (2013).","journal-title":"Clin Exp Immunol"},{"key":"12154_CR13","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1007\/s00441-010-1044-y","volume":"343","author":"LJ Quinton","year":"2011","unstructured":"Quinton, L. J. & Mizgerd, J. P. NF-kappaB and STAT3 signaling hubs for lung innate immunity. Cell Tissue Res 343, 153\u2013165, https:\/\/doi.org\/10.1007\/s00441-010-1044-y (2011).","journal-title":"Cell Tissue Res"},{"key":"12154_CR14","doi-asserted-by":"publisher","first-page":"1896","DOI":"10.4049\/jimmunol.178.3.1896","volume":"178","author":"LJ Quinton","year":"2007","unstructured":"Quinton, L. J. et al. Functions and regulation of NF-kappaB RelA during pneumococcal pneumonia. J Immunol 178, 1896\u20131903 (2007).","journal-title":"J Immunol"},{"key":"12154_CR15","doi-asserted-by":"publisher","first-page":"710","DOI":"10.1164\/rccm.200803-462OC","volume":"178","author":"MM Wurfel","year":"2008","unstructured":"Wurfel, M. M. et al. Toll-like receptor 1 polymorphisms affect innate immune responses and outcomes in sepsis. Am J Respir Crit Care Med 178, 710\u2013720, https:\/\/doi.org\/10.1164\/rccm.200803-462OC (2008).","journal-title":"Am J Respir Crit Care Med"},{"key":"12154_CR16","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1084\/jem.194.4.519","volume":"194","author":"P Ye","year":"2001","unstructured":"Ye, P. et al. Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense. J Exp Med 194, 519\u2013527 (2001).","journal-title":"J Exp Med"},{"key":"12154_CR17","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1128\/CMR.00052-09","volume":"23","author":"HJ Newton","year":"2010","unstructured":"Newton, H. J., Ang, D. K., van Driel, I. R. & Hartland, E. L. Molecular pathogenesis of infections caused by Legionella pneumophila. Clin Microbiol Rev 23, 274\u2013298, https:\/\/doi.org\/10.1128\/CMR.00052-09 (2010).","journal-title":"Clin Microbiol Rev"},{"key":"12154_CR18","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1146\/annurev.micro.54.1.567","volume":"54","author":"MS Swanson","year":"2000","unstructured":"Swanson, M. S. & Hammer, B. K. Legionella pneumophila pathogenesis: A fateful journey from amoebae to macrophages. Annu Rev Microbiol 54, 567\u2013613, https:\/\/doi.org\/10.1146\/annurev.micro.54.1.567 (2000).","journal-title":"Annu Rev Microbiol"},{"key":"12154_CR19","doi-asserted-by":"publisher","first-page":"36173","DOI":"10.1074\/jbc.M604638200","volume":"281","author":"B Opitz","year":"2006","unstructured":"Opitz, B. et al. Legionella pneumophila induces IFN beta in lung epithelial cells via IPS-1 and IRF3, which also control bacterial replication. J Biol Chem 281, 36173\u201336179, https:\/\/doi.org\/10.1074\/jbc.M604638200 (2006).","journal-title":"J Biol Chem"},{"key":"12154_CR20","doi-asserted-by":"publisher","first-page":"1632","DOI":"10.1111\/j.1462-5822.2012.01828.x","volume":"14","author":"A Prashar","year":"2012","unstructured":"Prashar, A. et al. Mechanism of invasion of lung epithelial cells by filamentous Legionella pneumophila. Cell Microbiol 14, 1632\u20131655, https:\/\/doi.org\/10.1111\/j.1462-5822.2012.01828.x (2012).","journal-title":"Cell Microbiol"},{"key":"12154_CR21","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1038\/nrmicro1967","volume":"7","author":"RR Isberg","year":"2009","unstructured":"Isberg, R. R., O\u2019Connor, T. J. & Heidtman, M. The Legionella pneumophila replication vacuole: making a cosy niche inside host cells. Nature reviews. Microbiology 7, 13\u201324, https:\/\/doi.org\/10.1038\/nrmicro1967 (2009).","journal-title":"Nature reviews. Microbiology"},{"key":"12154_CR22","doi-asserted-by":"publisher","first-page":"935","DOI":"10.1111\/cmi.12450","volume":"17","author":"I Finsel","year":"2015","unstructured":"Finsel, I. & Hilbi, H. Formation of a pathogen vacuole according to Legionella pneumophila: how to kill one bird with many stones. Cell Microbiol 17, 935\u2013950, https:\/\/doi.org\/10.1111\/cmi.12450 (2015).","journal-title":"Cell Microbiol"},{"key":"12154_CR23","unstructured":"Eberhardt, M. et al. In Systems Medicine (eds Ulf Schmitz & Olaf Wolkenhauer) 135\u2013179 (Springer New York, 2016)."},{"key":"12154_CR24","doi-asserted-by":"publisher","first-page":"692","DOI":"10.1038\/nri2634","volume":"9","author":"R Medzhitov","year":"2009","unstructured":"Medzhitov, R. & Horng, T. Transcriptional control of the inflammatory response. Nat Rev Immunol 9, 692\u2013703, https:\/\/doi.org\/10.1038\/nri2634 (2009).","journal-title":"Nat Rev Immunol"},{"key":"12154_CR25","doi-asserted-by":"publisher","first-page":"833","DOI":"10.1016\/j.cell.2010.01.037","volume":"140","author":"ST Smale","year":"2010","unstructured":"Smale, S. T. Selective transcription in response to an inflammatory stimulus. Cell 140, 833\u2013844, https:\/\/doi.org\/10.1016\/j.cell.2010.01.037 (2010).","journal-title":"Cell"},{"key":"12154_CR26","doi-asserted-by":"publisher","first-page":"867","DOI":"10.1189\/jlb.0905505","volume":"79","author":"CH Li","year":"2006","unstructured":"Li, C. H., Wang, J. H. & Redmond, H. P. Bacterial lipoprotein-induced self-tolerance and cross-tolerance to LPS are associated with reduced IRAK-1 expression and MyD88-IRAK complex formation. J Leukoc Biol 79, 867\u2013875, https:\/\/doi.org\/10.1189\/jlb.0905505 (2006).","journal-title":"J Leukoc Biol"},{"key":"12154_CR27","doi-asserted-by":"publisher","first-page":"13636","DOI":"10.1074\/jbc.M600620200","volume":"281","author":"H Li","year":"2006","unstructured":"Li, H., Kobayashi, M., Blonska, M., You, Y. & Lin, X. Ubiquitination of RIP is required for tumor necrosis factor alpha-induced NF-kappaB activation. J Biol Chem 281, 13636\u201313643, https:\/\/doi.org\/10.1074\/jbc.M600620200 (2006).","journal-title":"J Biol Chem"},{"key":"12154_CR28","doi-asserted-by":"publisher","first-page":"12481","DOI":"10.1073\/pnas.0605298103","volume":"103","author":"KD Taganov","year":"2006","unstructured":"Taganov, K. D., Boldin, M. P., Chang, K. J. & Baltimore, D. NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci USA 103, 12481\u201312486 (2006).","journal-title":"Proc Natl Acad Sci USA"},{"key":"12154_CR29","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1172\/JCI111493","volume":"74","author":"TW Nash","year":"1984","unstructured":"Nash, T. W., Libby, D. M. & Horwitz, M. A. Interaction between the Legionnaires-Disease Bacterium (Legionella Pneumophila) and Human Alveolar Macrophages - Influence of Antibody, Lymphokines, and Hydrocortisone. J Clin Invest 74, 771\u2013782, https:\/\/doi.org\/10.1172\/Jci111493 (1984).","journal-title":"J Clin Invest"},{"key":"12154_CR30","doi-asserted-by":"publisher","first-page":"1984","DOI":"10.1128\/IAI.01077-10","volume":"79","author":"K McCoy-Simandle","year":"2011","unstructured":"McCoy-Simandle, K. et al. Legionella pneumophila Type II Secretion Dampens the Cytokine Response of Infected Macrophages and Epithelia. Infect Immun 79, 1984\u20131997, https:\/\/doi.org\/10.1128\/Iai.01077-10 (2011).","journal-title":"Infect Immun"},{"key":"12154_CR31","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1128\/IAI.00703-13","volume":"82","author":"J Jager","year":"2014","unstructured":"Jager, J. et al. Human lung tissue explants reveal novel interactions during Legionella pneumophila infections. Infect Immun 82, 275\u2013285, https:\/\/doi.org\/10.1128\/IAI.00703-13 (2014).","journal-title":"Infect Immun"},{"key":"12154_CR32","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1183\/09031936.00141005","volume":"29","author":"B Schmeck","year":"2007","unstructured":"Schmeck, B. et al. Legionella pneumophila-induced NF-kappaB- and MAPK-dependent cytokine release by lung epithelial cells. Eur Respir J 29, 25\u201333, https:\/\/doi.org\/10.1183\/09031936.00141005 (2007).","journal-title":"Eur Respir J"},{"key":"12154_CR33","doi-asserted-by":"publisher","first-page":"811","DOI":"10.4049\/jimmunol.1004143","volume":"188","author":"U Koppe","year":"2012","unstructured":"Koppe, U. et al. Streptococcus pneumoniae stimulates a STING- and IFN regulatory factor 3-dependent type I IFN production in macrophages, which regulates RANTES production in macrophages, cocultured alveolar epithelial cells, and mouse lungs. J Immunol 188, 811\u2013817, https:\/\/doi.org\/10.4049\/jimmunol.1004143 (2012).","journal-title":"J Immunol"},{"key":"12154_CR34","first-page":"472","volume":"73","author":"RA Ribeiro","year":"1991","unstructured":"Ribeiro, R. A., Flores, C. A., Cunha, F. Q. & Ferreira, S. H. IL-8 causes in vivo neutrophil migration by a cell-dependent mechanism. Immunology 73, 472\u2013477 (1991).","journal-title":"Immunology"},{"key":"12154_CR35","first-page":"65","volume":"72","author":"WB Smith","year":"1991","unstructured":"Smith, W. B., Gamble, J. R., Clark-Lewis, I. & Vadas, M. A. Interleukin-8 induces neutrophil transendothelial migration. Immunology 72, 65\u201372 (1991).","journal-title":"Immunology"},{"key":"12154_CR36","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1159\/000354173","volume":"59","author":"R Shaykhiev","year":"2013","unstructured":"Shaykhiev, R. & Crystal, R. G. Innate immunity and chronic obstructive pulmonary disease: a mini-review. Gerontology 59, 481\u2013489, https:\/\/doi.org\/10.1159\/000354173 (2013).","journal-title":"Gerontology"},{"key":"12154_CR37","doi-asserted-by":"publisher","first-page":"6024","DOI":"10.4049\/jimmunol.1500124","volume":"194","author":"RJ Jose","year":"2015","unstructured":"Jose, R. J. et al. Regulation of neutrophilic inflammation by proteinase-activated receptor 1 during bacterial pulmonary infection. J Immunol 194, 6024\u20136034, https:\/\/doi.org\/10.4049\/jimmunol.1500124 (2015).","journal-title":"J Immunol"},{"key":"12154_CR38","doi-asserted-by":"publisher","first-page":"1586","DOI":"10.1128\/IAI.01579-06","volume":"75","author":"M Marks","year":"2007","unstructured":"Marks, M. et al. Influence of neutropenia on the course of serotype 8 pneumococcal pneumonia in mice. Infect Immun 75, 1586\u20131597, https:\/\/doi.org\/10.1128\/IAI.01579-06 (2007).","journal-title":"Infect Immun"},{"key":"12154_CR39","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1007\/s00005-011-0155-9","volume":"60","author":"M Morris","year":"2012","unstructured":"Morris, M. & Li, L. Molecular mechanisms and pathological consequences of endotoxin tolerance and priming. Arch Immunol Ther Exp (Warsz) 60, 13\u201318, https:\/\/doi.org\/10.1007\/s00005-011-0155-9 (2012).","journal-title":"Arch Immunol Ther Exp (Warsz)"},{"key":"12154_CR40","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1038\/cmi.2011.26","volume":"8","author":"MA Nahid","year":"2011","unstructured":"Nahid, M. A., Satoh, M. & Chan, E. K. MicroRNA in TLR signaling and endotoxin tolerance. Cell Mol Immunol 8, 388\u2013403, https:\/\/doi.org\/10.1038\/cmi.2011.26 (2011).","journal-title":"Cell Mol Immunol"},{"key":"12154_CR41","doi-asserted-by":"publisher","first-page":"972","DOI":"10.1038\/nature05836","volume":"447","author":"SL Foster","year":"2007","unstructured":"Foster, S. L., Hargreaves, D. C. & Medzhitov, R. Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature 447, 972\u2013978, https:\/\/doi.org\/10.1038\/nature05836 (2007).","journal-title":"Nature"},{"key":"12154_CR42","doi-asserted-by":"crossref","first-page":"3936","DOI":"10.4049\/jimmunol.163.7.3936","volume":"163","author":"MI Wickremasinghe","year":"1999","unstructured":"Wickremasinghe, M. I., Thomas, L. H. & Friedland, J. S. Pulmonary epithelial cells are a source of IL-8 in the response to Mycobacterium tuberculosis: essential role of IL-1 from infected monocytes in a NF-kappa B-dependent network. Journal of immunology 163, 3936\u20133947 (1999).","journal-title":"Journal of immunology"},{"key":"12154_CR43","doi-asserted-by":"publisher","first-page":"12555","DOI":"10.1093\/nar\/gku1033","volume":"42","author":"F Bollmann","year":"2014","unstructured":"Bollmann, F. et al. Resveratrol post-transcriptionally regulates pro-inflammatory gene expression via regulation of KSRP RNA binding activity. Nucleic Acids Res 42, 12555\u201312569, https:\/\/doi.org\/10.1093\/nar\/gku1033 (2014).","journal-title":"Nucleic Acids Res"},{"key":"12154_CR44","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1124\/jpet.109.151423","volume":"330","author":"EM King","year":"2009","unstructured":"King, E. M. et al. Regulation of tristetraprolin expression by interleukin-1 beta and dexamethasone in human pulmonary epithelial cells: roles for nuclear factor-kappa B and p38 mitogen-activated protein kinase. The Journal of pharmacology and experimental therapeutics 330, 575\u2013585, https:\/\/doi.org\/10.1124\/jpet.109.151423 (2009).","journal-title":"The Journal of pharmacology and experimental therapeutics"},{"key":"12154_CR45","doi-asserted-by":"publisher","first-page":"524","DOI":"10.1038\/mi.2012.28","volume":"5","author":"M Habibzay","year":"2012","unstructured":"Habibzay, M., Saldana, J. I., Goulding, J., Lloyd, C. M. & Hussell, T. Altered regulation of Toll-like receptor responses impairs antibacterial immunity in the allergic lung. Mucosal Immunol 5, 524\u2013534, https:\/\/doi.org\/10.1038\/mi.2012.28 (2012).","journal-title":"Mucosal Immunol"},{"key":"12154_CR46","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1111\/j.1365-2249.2009.04048.x","volume":"159","author":"N Oshima","year":"2010","unstructured":"Oshima, N. et al. A20 is an early responding negative regulator of Toll-like receptor 5 signalling in intestinal epithelial cells during inflammation. Clin Exp Immunol 159, 185\u2013198, https:\/\/doi.org\/10.1111\/j.1365-2249.2009.04048.x (2010).","journal-title":"Clin Exp Immunol"},{"key":"12154_CR47","doi-asserted-by":"publisher","first-page":"2736","DOI":"10.4049\/jimmunol.173.4.2736","volume":"173","author":"M Siedlar","year":"2004","unstructured":"Siedlar, M. et al. Tolerance induced by the lipopeptide Pam(3)Cys is due to ablation of IL-1R-associated kinase-1. J Immunol 173, 2736\u20132745 (2004).","journal-title":"J Immunol"},{"key":"12154_CR48","doi-asserted-by":"publisher","first-page":"314","DOI":"10.1038\/icb.2011.37","volume":"90","author":"CH Li","year":"2012","unstructured":"Li, C. H., Liu, J. H., An, M. B., Redmond, H. P. & Wang, J. H. Bacterial lipoprotein-induced tolerance is reversed by overexpression of IRAK-1. Immunol Cell Biol 90, 314\u2013320, https:\/\/doi.org\/10.1038\/icb.2011.37 (2012).","journal-title":"Immunol Cell Biol"},{"key":"12154_CR49","doi-asserted-by":"publisher","first-page":"872","DOI":"10.1165\/rcmb.2015-0057OC","volume":"53","author":"J Neagos","year":"2015","unstructured":"Neagos, J. et al. Epigenetic Regulation of Tolerance to Toll-Like Receptor Ligands in Alveolar Epithelial Cells. Am J Respir Cell Mol Biol 53, 872\u2013881, https:\/\/doi.org\/10.1165\/rcmb.2015-0057OC (2015).","journal-title":"Am J Respir Cell Mol Biol"},{"key":"12154_CR50","doi-asserted-by":"publisher","first-page":"D239","DOI":"10.1093\/nar\/gkv1258","volume":"44","author":"CH Chou","year":"2016","unstructured":"Chou, C. H. et al. miRTarBase 2016: updates to the experimentally validated miRNA-target interactions database. Nucleic acids research 44, D239\u2013247, https:\/\/doi.org\/10.1093\/nar\/gkv1258 (2016).","journal-title":"Nucleic acids research"},{"key":"12154_CR51","doi-asserted-by":"publisher","first-page":"29037","DOI":"10.1074\/jbc.M103815200","volume":"276","author":"LE Jensen","year":"2001","unstructured":"Jensen, L. E. & Whitehead, A. S. IRAK1b, a novel alternative splice variant of interleukin-1 receptor-associated kinase (IRAK), mediates interleukin-1 signaling and has prolonged stability. J Biol Chem 276, 29037\u201329044, https:\/\/doi.org\/10.1074\/jbc.M103815200 (2001).","journal-title":"J Biol Chem"},{"key":"12154_CR52","doi-asserted-by":"publisher","first-page":"4125","DOI":"10.4049\/jimmunol.179.6.4125","volume":"179","author":"G Liu","year":"2007","unstructured":"Liu, G., Tsuruta, Y., Gao, Z., Park, Y. J. & Abraham, E. Variant IL-1 receptor-associated kinase-1 mediates increased NF-kappa B activity. J Immunol 179, 4125\u20134134 (2007).","journal-title":"J Immunol"},{"key":"12154_CR53","doi-asserted-by":"publisher","first-page":"1335","DOI":"10.1164\/rccm.200603-341OC","volume":"173","author":"J Arcaroli","year":"2006","unstructured":"Arcaroli, J. et al. Variant IRAK-1 haplotype is associated with increased nuclear factor-kappa B activation and worse outcomes in sepsis. Am J Respir Crit Care Med 173, 1335\u20131341, https:\/\/doi.org\/10.1164\/rccm.200603-341OC (2006).","journal-title":"Am J Respir Crit Care Med"},{"key":"12154_CR54","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1006\/meth.2001.1262","volume":"25","author":"KJ Livak","year":"2001","unstructured":"Livak, K. J. & Schmittgen, T. D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(T)(-Delta Delta C) method. Methods 25, 402\u2013408, https:\/\/doi.org\/10.1006\/meth.2001.1262 (2001).","journal-title":"Methods"},{"key":"12154_CR55","doi-asserted-by":"publisher","first-page":"514","DOI":"10.1093\/bioinformatics\/bti799","volume":"22","author":"H Schmidt","year":"2006","unstructured":"Schmidt, H. & Jirstrand, M. Systems Biology Toolbox for MATLAB: a computational platform for research in systems biology. Bioinformatics 22, 514\u2013515, https:\/\/doi.org\/10.1093\/bioinformatics\/bti799 (2006).","journal-title":"Bioinformatics"},{"key":"12154_CR56","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-7-483","volume":"7","author":"M Rodriguez-Fernandez","year":"2006","unstructured":"Rodriguez-Fernandez, M., Egea, J. A. & Banga, J. R. Novel metaheuristic for parameter estimation in nonlinear dynamic biological systems. BMC Bioinformatics 7, 483, https:\/\/doi.org\/10.1186\/1471-2105-7-483 (2006).","journal-title":"BMC Bioinformatics"},{"key":"12154_CR57","unstructured":"Press, W. H., Teukolsky, S., Vetterling, W. T. & Flannery, B.P. In Numerical Recipes in C: The Art of Scientific Computing Ch. 408-412, (Cambridge University Press, 1992)."},{"key":"12154_CR58","doi-asserted-by":"publisher","first-page":"1923","DOI":"10.1093\/bioinformatics\/btp358","volume":"25","author":"A Raue","year":"2009","unstructured":"Raue, A. et al. Structural and practical identifiability analysis of partially observed dynamical models by exploiting the profile likelihood. Bioinformatics 25, 1923\u20131929, https:\/\/doi.org\/10.1093\/bioinformatics\/btp358 (2009).","journal-title":"Bioinformatics"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-12154-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-12154-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-12154-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T21:31:11Z","timestamp":1692999071000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-12154-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,9,20]]},"references-count":58,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["12154"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-12154-4","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,9,20]]},"assertion":[{"value":"3 March 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 September 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 September 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"11988"}}