{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T13:38:09Z","timestamp":1773409089346,"version":"3.50.1"},"reference-count":21,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2014,4,24]],"date-time":"2014-04-24T00:00:00Z","timestamp":1398297600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"},{"start":{"date-parts":[[2014,4,24]],"date-time":"2014-04-24T00:00:00Z","timestamp":1398297600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Arthritis Res Ther"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                        <jats:title>Introduction<\/jats:title>\n                        <jats:p>Our objective was to examine the role of the janus-activated kinase (JAK) pathway in the modulation of tumor necrosis factor-\u03b1 (TNF)-induced-IL-18 bioactivity by reduction of caspase-1 function.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Methods<\/jats:title>\n                        <jats:p>Caspase-1 expression in rheumatoid arthritis (RA) synovial fibroblasts treated with TNF was assessed by qRT-PCR and Western blot. Interleukin (IL)-18 was assessed by enzyme-linked immunosorbent assay (ELISA) in cell lysates and conditioned media and detected by immunofluorescence (IF) staining in RA synovial fibroblasts. The critical pathways for TNF-induced caspase-1 expression were determined by using chemical inhibitors of signaling followed by TNF stimulation. IL-18 bioactivity was assessed using human myelomonocytic KG-1 cells.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Results<\/jats:title>\n                        <jats:p>TNF induced RA synovial fibroblast caspase-1 expression at the protein level in a time-dependant manner (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05). Blocking the JAK pathway reduced TNF-induced-caspase-1 expression at the transcriptional and protein levels by approximately 60% and 40%, respectively (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05). Blocking the JAK pathway reduced TNF-induced-caspase-1 expression at the transcriptional, protein, and activity levels by approximately 60%, 40%, and 53%, respectively (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05). We then confirmed by IF that TNF-induced IL-18 and investigated roles of the ERK1\/2 and JAK pathways. Blocking the JAK pathway, TNF induced intracytoplasmic granular IL-18 expression suggesting a defect of caspase-1. Finally, blocking the JAK pathway, we observed a reduction of IL-18 bioactivity by 52% in RA synovial fibroblasts (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05).<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Conclusions<\/jats:title>\n                        <jats:p>These results provide a new way to regulate TNF-induced-IL-18 bioactivity by blocking capase-1. These data present a novel role for JAK inhibition in RA patients and emphasize JAK inhibition use as a new therapeutic option in RA management.<\/jats:p>\n                     <\/jats:sec>","DOI":"10.1186\/ar4551","type":"journal-article","created":{"date-parts":[[2014,4,24]],"date-time":"2014-04-24T10:00:16Z","timestamp":1398333616000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Blocking the janus-activated kinase pathway reduces tumor necrosis factor alpha-induced interleukin-18 bioactivity by caspase-1 inhibition"],"prefix":"10.1186","volume":"16","author":[{"given":"Hubert","family":"Marotte","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pei-Suen","family":"Tsou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatiana","family":"Fedorova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adam J","family":"Pinney","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin","family":"Lewis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alisa E","family":"Koch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2014,4,24]]},"reference":[{"key":"4269_CR1","doi-asserted-by":"publisher","first-page":"1393","DOI":"10.1172\/JCI7317","volume":"104","author":"JA Gracie","year":"1999","unstructured":"Gracie JA, Forsey RJ, Chan WL, Gilmour A, Leung BP, Greer MR, Kennedy K, Carter R, Wei XQ, Xu D, Field M, Foulis A, Liew FY, McInnes IB: A proinflammatory role for IL-18 in rheumatoid arthritis. J Clin Invest. 1999, 104: 1393-1401. 10.1172\/JCI7317.","journal-title":"J Clin Invest"},{"key":"4269_CR2","doi-asserted-by":"publisher","first-page":"34679","DOI":"10.1074\/jbc.M206337200","volume":"277","author":"JC Morel","year":"2002","unstructured":"Morel JC, Park CC, Zhu K, Kumar P, Ruth JH, Koch AE: Signal transduction pathways involved in rheumatoid arthritis synovial fibroblast interleukin-18-induced vascular cell adhesion molecule-1 expression. J Biol Chem. 2002, 277: 34679-34691. 10.1074\/jbc.M206337200.","journal-title":"J Biol Chem"},{"key":"4269_CR3","doi-asserted-by":"publisher","first-page":"2204","DOI":"10.1136\/ard.2009.127241","volume":"69","author":"MA Amin","year":"2010","unstructured":"Amin MA, Rabquer BJ, Mansfield PJ, Ruth JH, Marotte H, Haas CS, Reamer EN, Koch AE: Interleukin 18 induces angiogenesis in vitro and in vivo via Src and Jnk kinases. Ann Rheum Dis. 2010, 69: 2204-2212. 10.1136\/ard.2009.127241.","journal-title":"Ann Rheum Dis"},{"key":"4269_CR4","doi-asserted-by":"publisher","first-page":"R118","DOI":"10.1186\/ar3055","volume":"12","author":"JH Ruth","year":"2010","unstructured":"Ruth JH, Park CC, Amin MA, Lesch C, Marotte H, Shahrara S, Koch AE: Interleukin-18 as an in vivo mediator of monocyte recruitment in rodent models of rheumatoid arthritis. Arthritis Res Ther. 2010, 12: R118-10.1186\/ar3055.","journal-title":"Arthritis Res Ther"},{"key":"4269_CR5","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1002\/art.27269","volume":"62","author":"H Marotte","year":"2010","unstructured":"Marotte H, Ahmed S, Ruth JH, Koch AE: Blocking ERK-1\/2 reduces tumor necrosis factor alpha-induced interleukin-18 bioactivity in rheumatoid arthritis synovial fibroblasts by induction of interleukin-18 binding protein A. Arthritis Rheum. 2010, 62: 722-731. 10.1002\/art.27269.","journal-title":"Arthritis Rheum"},{"key":"4269_CR6","doi-asserted-by":"publisher","first-page":"3253","DOI":"10.1002\/art.30583","volume":"63","author":"H Marotte","year":"2011","unstructured":"Marotte H, Tsou PS, Rabquer BJ, Pinney AJ, Fedorova T, Lalwani N, Koch AE: Blocking of interferon regulatory factor 1 reduces tumor necrosis factor alpha-induced interleukin-18 bioactivity in rheumatoid arthritis synovial fibroblasts by induction of interleukin-18 binding protein a: Role of the nuclear interferon regulatory factor 1-NF-kappaB-c-jun complex. Arthritis Rheum. 2011, 63: 3253-3262. 10.1002\/art.30583.","journal-title":"Arthritis Rheum"},{"key":"4269_CR7","doi-asserted-by":"publisher","first-page":"1812","DOI":"10.1111\/j.1462-5822.2006.00751.x","volume":"8","author":"SL Fink","year":"2006","unstructured":"Fink SL, Cookson BT: Caspase-1-dependent pore formation during pyroptosis leads to osmotic lysis of infected host macrophages. Cell Microbiol. 2006, 8: 1812-1825. 10.1111\/j.1462-5822.2006.00751.x.","journal-title":"Cell Microbiol"},{"key":"4269_CR8","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1016\/j.cell.2004.05.004","volume":"117","author":"F Martinon","year":"2004","unstructured":"Martinon F, Tschopp J: Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory diseases. Cell. 2004, 117: 561-574. 10.1016\/j.cell.2004.05.004.","journal-title":"Cell"},{"key":"4269_CR9","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1038\/ni.1703","volume":"10","author":"L Franchi","year":"2009","unstructured":"Franchi L, Eigenbrod T, Munoz-Planillo R, Nunez G: The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis. Nat Immunol. 2009, 10: 241-247.","journal-title":"Nat Immunol"},{"key":"4269_CR10","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1038\/nrd3800","volume":"11","author":"CA Dinarello","year":"2012","unstructured":"Dinarello CA, Simon A, van der Meer JW: Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov. 2012, 11: 633-652. 10.1038\/nrd3800.","journal-title":"Nat Rev Drug Discov"},{"key":"4269_CR11","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1126\/science.275.5297.206","volume":"275","author":"Y Gu","year":"1997","unstructured":"Gu Y, Kuida K, Tsutsui H, Ku G, Hsiao K, Fleming MA, Hayashi N, Higashino K, Okamura H, Nakanishi K, Kurimoto M, Tanimoto T, Flavell RA, Sato V, Harding MW, Livingston DJ, Su MS: Activation of interferon-gamma inducing factor mediated by interleukin-1 beta converting enzyme. Science. 1997, 275: 206-209. 10.1126\/science.275.5297.206.","journal-title":"Science"},{"key":"4269_CR12","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1517\/14728222.12.2.171","volume":"12","author":"CJ Malemud","year":"2008","unstructured":"Malemud CJ, Miller AH: Pro-inflammatory cytokine-induced SAPK\/MAPK and JAK\/STAT in rheumatoid arthritis and the new anti-depression drugs. Expert Opin Ther Targets. 2008, 12: 171-183. 10.1517\/14728222.12.2.171.","journal-title":"Expert Opin Ther Targets"},{"key":"4269_CR13","doi-asserted-by":"publisher","first-page":"2256","DOI":"10.1073\/pnas.96.5.2256","volume":"96","author":"AJ Puren","year":"1999","unstructured":"Puren AJ, Fantuzzi G, Dinarello CA: Gene expression, synthesis, and secretion of interleukin 18 and interleukin 1beta are differentially regulated in human blood mononuclear cells and mouse spleen cells. Proc Natl Acad Sci USA. 1999, 96: 2256-2261. 10.1073\/pnas.96.5.2256.","journal-title":"Proc Natl Acad Sci USA"},{"key":"4269_CR14","doi-asserted-by":"publisher","first-page":"1618","DOI":"10.1002\/eji.201142173","volume":"42","author":"F Bellora","year":"2012","unstructured":"Bellora F, Castriconi R, Doni A, Cantoni C, Moretta L, Mantovani A, Moretta A, Bottino C: M-CSF induces the expression of a membrane-bound form of IL-18 in a subset of human monocytes differentiating in vitro toward macrophages. Eur J Immunol. 2012, 42: 1618-1626. 10.1002\/eji.201142173.","journal-title":"Eur J Immunol"},{"key":"4269_CR15","doi-asserted-by":"publisher","first-page":"1433","DOI":"10.1084\/jem.163.6.1433","volume":"163","author":"CA Dinarello","year":"1986","unstructured":"Dinarello CA, Cannon JG, Wolff SM, Bernheim HA, Beutler B, Cerami A, Figari IS, Palladino MA, O\u2019Connor JV: Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1. J Exp Med. 1986, 163: 1433-1450. 10.1084\/jem.163.6.1433.","journal-title":"J Exp Med"},{"key":"4269_CR16","doi-asserted-by":"crossref","first-page":"2742","DOI":"10.4049\/jimmunol.160.6.2742","volume":"160","author":"D Guo","year":"1998","unstructured":"Guo D, Dunbar JD, Yang CH, Pfeffer LM, Donner DB: Induction of Jak\/STAT signaling by activation of the type 1 TNF receptor. J Immunol. 1998, 160: 2742-2750.","journal-title":"J Immunol"},{"key":"4269_CR17","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1136\/ard.2011.150284","volume":"71","author":"S Rosengren","year":"2012","unstructured":"Rosengren S, Corr M, Firestein GS, Boyle DL: The JAK inhibitor CP-690,550 (tofacitinib) inhibits TNF-induced chemokine expression in fibroblast-like synoviocytes: autocrine role of type I interferon. Ann Rheum Dis. 2012, 71: 440-447. 10.1136\/ard.2011.150284.","journal-title":"Ann Rheum Dis"},{"key":"4269_CR18","doi-asserted-by":"publisher","first-page":"3856","DOI":"10.1002\/art.37691","volume":"64","author":"A Yarilina","year":"2012","unstructured":"Yarilina A, Xu K, Chan C, Ivashkiv LB: Regulation of inflammatory responses in tumor necrosis factor-activated and rheumatoid arthritis synovial macrophages by JAK inhibitors. Arthritis Rheum. 2012, 64: 3856-3866. 10.1002\/art.37691.","journal-title":"Arthritis Rheum"},{"key":"4269_CR19","doi-asserted-by":"publisher","first-page":"5298","DOI":"10.4049\/jimmunol.0902819","volume":"184","author":"JS Fridman","year":"2010","unstructured":"Fridman JS, Scherle PA, Collins R, Burn TC, Li Y, Li J, Covington MB, Thomas B, Collier P, Favata MF, Wen X, Shi J, McGee R, Haley PJ, Shepard S, Rodgers JD, Yeleswaram S, Hollis G, Newton RC, Metcalf B, Friedman SM, Vaddi K: Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: preclinical characterization of INCB028050. J Immunol. 2010, 184: 5298-5307. 10.4049\/jimmunol.0902819.","journal-title":"J Immunol"},{"key":"4269_CR20","doi-asserted-by":"publisher","first-page":"3531","DOI":"10.1002\/art.34649","volume":"64","author":"TP LaBranche","year":"2012","unstructured":"LaBranche TP, Jesson MI, Radi ZA, Storer CE, Guzova JA, Bonar SL, Thompson JM, Happa FA, Stewart ZS, Zhan Y, Bollinger CS, Bansal PN, Wellen JW, Wilkie DP, Bailey SA, Symanowicz PT, Hegen M, Head RD, Kishore N, Mbalaviele G, Meyer DM: JAK inhibition with tofacitinib suppresses arthritic joint structural damage through decreased RANKL production. Arthritis Rheum. 2012, 64: 3531-3542. 10.1002\/art.34649.","journal-title":"Arthritis Rheum"},{"key":"4269_CR21","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1002\/art.33383","volume":"64","author":"R Fleischmann","year":"2012","unstructured":"Fleischmann R, Cutolo M, Genovese MC, Lee EB, Kanik KS, Sadis S, Connell CA, Gruben D, Krishnaswami S, Wallenstein G, Wilkinson BE, Zwillich SH: Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs. Arthritis Rheum. 2012, 64: 617-629. 10.1002\/art.33383.","journal-title":"Arthritis Rheum"}],"container-title":["Arthritis Research &amp; Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/ar4551.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/ar4551\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/ar4551.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,8]],"date-time":"2024-10-08T10:15:03Z","timestamp":1728382503000},"score":1,"resource":{"primary":{"URL":"https:\/\/arthritis-research.biomedcentral.com\/articles\/10.1186\/ar4551"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,4,24]]},"references-count":21,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2014,4]]}},"alternative-id":["4269"],"URL":"https:\/\/doi.org\/10.1186\/ar4551","relation":{},"ISSN":["1478-6354"],"issn-type":[{"value":"1478-6354","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,4,24]]},"assertion":[{"value":"14 May 2013","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 March 2014","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 April 2014","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"R102"}}