{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T01:57:21Z","timestamp":1790819841406,"version":"4.1.0"},"reference-count":31,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2012,11,13]],"date-time":"2012-11-13T00:00:00Z","timestamp":1352764800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"},{"start":{"date-parts":[[2012,11,13]],"date-time":"2012-11-13T00:00:00Z","timestamp":1352764800000},"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><jats:title>Introduction<\/jats:title><jats:p>Interleukin (IL)-32 and IL-17 play critical roles in pro-inflammatory responses and are highly expressed in the synovium of patients with rheumatoid arthritis (RA). We investigated the relations between these two cytokines (IL-17 and IL-32) for their ability to induce each other and to stimulate osteoclasts in RA fibroblast-like synoviocytes (FLSs) and T cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>FLSs were isolated through surgical synovectomy obtained from patients with RA or osteoarthritis (OA). Real-time PCR were performed to evaluate the expression of IL-32, IL-17 and osteoclast-related genes. Immunohistochemical staining and tartrate-resistant acid phosphatase (TRAP) staining were performed to determine the distribution of inflammatory cytokines and the presence of osteoclastogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>IL-17 induced the expression of IL-32 in the FLSs from RA patients, as assessed by microarray. IL-32 production was increased by IL-17. IL-32 in the FLSs from RA patients induced the production of IL-17 in CD4<jats:sup>+<\/jats:sup>T cells. IL-32 and IL-17 were colocalized near TRAP-positive areas in joint specimens. IL-17 and IL-32 synergistically induced the differentiation of osteoclasts, as demonstrated by the expression of osteoclast-related genes. IL-32 and IL-17 also could induce resorption by osteoclasts in a RANKL-dependent manner.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>IL-17 affected the expression of IL-32 in FLSs of RA patients and IL-32 induced the production of IL-17 in CD4+ T cells. Both IL-17 and IL-32 cytokines can reciprocally influence each other's production and amplify the function of osteoclastogenesis in the in RA synovium. Separately, IL-17 and IL-32 each stimulated osteoclastogenesis without RANKL. Together, the two cytokines synergistically amplified the differentiation of osteoclasts, independent of RANKL stimulation.<\/jats:p><\/jats:sec>","DOI":"10.1186\/ar4089","type":"journal-article","created":{"date-parts":[[2012,11,13]],"date-time":"2012-11-13T15:14:21Z","timestamp":1352819661000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":99,"title":["IL-32 and IL-17 interact and have the potential to aggravate osteoclastogenesis in rheumatoid arthritis"],"prefix":"10.1186","volume":"14","author":[{"given":"Young-Mee","family":"Moon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo-Young","family":"Yoon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang-Mi","family":"Her","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hye-Joa","family":"Oh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae-Seon","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyoung-Woon","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seon-Yeong","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun-Ju","family":"Woo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyung-Su","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung-Hwan","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ho-Youn","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mi-La","family":"Cho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2012,11,13]]},"reference":[{"key":"3830_CR1","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1084\/jem.173.3.569","volume":"173","author":"R Bucala","year":"1991","unstructured":"Bucala R, Ritchlin C, Winchester R, Cerami A: Constitutive production of inflammatory and mitogenic cytokines by rheumatoid synovial fibroblasts. J Exp Med. 1991, 173: 569-574. 10.1084\/jem.173.3.569.","journal-title":"J Exp Med"},{"key":"3830_CR2","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1056\/NEJM197509112931101","volume":"293","author":"JA Van Boxel","year":"1975","unstructured":"Van Boxel JA, Paget SA: Predominantly T-cell infiltrate in rheumatoid synovial membranes. N Engl J Med. 1975, 293: 517-520. 10.1056\/NEJM197509112931101.","journal-title":"N Engl J Med"},{"key":"3830_CR3","doi-asserted-by":"publisher","first-page":"2270","DOI":"10.4049\/jimmunol.166.4.2270","volume":"166","author":"Y Yamamura","year":"2001","unstructured":"Yamamura Y, Gupta R, Morita Y, He X, Pai R, Endres J, Freiberg A, Chung K, Fox DA: Effector function of resting T cells: activation of synovial fibroblasts. J Immunol. 2001, 166: 2270-2275.","journal-title":"J Immunol"},{"key":"3830_CR4","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1084\/jem.20041257","volume":"201","author":"CL Langrish","year":"2005","unstructured":"Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, Kastelein RA, Cua DJ: IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005, 201: 233-240. 10.1084\/jem.20041257.","journal-title":"J Exp Med"},{"key":"3830_CR5","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1172\/JCI5703","volume":"103","author":"S Kotake","year":"1999","unstructured":"Kotake S, Udagawa N, Takahashi N, Matsuzaki K, Itoh K, Ishiyama S, Saito S, Inoue K, Kamatani N, Gillespie MT, Martin TJ, Suda T: IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest. 1999, 103: 1345-1352. 10.1172\/JCI5703.","journal-title":"J Clin Invest"},{"key":"3830_CR6","doi-asserted-by":"publisher","first-page":"2655","DOI":"10.4049\/jimmunol.170.5.2655","volume":"170","author":"E Lubberts","year":"2003","unstructured":"Lubberts E, van den Bersselaar L, Oppers-Walgreen B, Schwarzenberger P, Coenen-de Roo CJ, Kolls JK, Joosten LA, van den Berg WB: IL-17 promotes bone erosion in murine collagen-induced arthritis through loss of the receptor activator of NF-kappa B ligand\/osteoprotegerin balance. J Immunol. 2003, 170: 2655-2662.","journal-title":"J Immunol"},{"key":"3830_CR7","doi-asserted-by":"publisher","first-page":"1122","DOI":"10.1002\/art.21749","volume":"54","author":"BW Kirkham","year":"2006","unstructured":"Kirkham BW, Lassere MN, Edmonds JP, Juhasz KM, Bird PA, Lee CS, Shnier R, Portek IJ: Synovial membrane cytokine expression is predictive of joint damage progression in rheumatoid arthritis: a two-year prospective study (the DAMAGE study cohort). Arthritis Rheum. 2006, 54: 1122-1131. 10.1002\/art.21749.","journal-title":"Arthritis Rheum"},{"key":"3830_CR8","doi-asserted-by":"publisher","first-page":"R120","DOI":"10.1186\/ar1038","volume":"6","author":"SY Hwang","year":"2004","unstructured":"Hwang SY, Kim JY, Kim KW, Park MK, Moon Y, Kim WU, Kim HY: IL-17 induces production of IL-6 and IL-8 in rheumatoid arthritis synovial fibroblasts via NF-kappaB- and PI3-kinase\/Akt-dependent pathways. Arthritis Res Ther. 2004, 6: R120-128. 10.1186\/ar1038.","journal-title":"Arthritis Res Ther"},{"key":"3830_CR9","doi-asserted-by":"publisher","first-page":"237","DOI":"10.3858\/emm.2008.40.2.237","volume":"40","author":"ML Cho","year":"2008","unstructured":"Cho ML, Jung YO, Kim KW, Park MK, Oh HJ, Ju JH, Cho YG, Min JK, Kim SI, Park SH, Kim HY: IL-17 induces the production of IL-16 in rheumatoid arthritis. Exp Mol Med. 2008, 40: 237-245. 10.3858\/emm.2008.40.2.237.","journal-title":"Exp Mol Med"},{"key":"3830_CR10","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1093\/rheumatology\/kel159","volume":"46","author":"HR Kim","year":"2007","unstructured":"Kim HR, Cho ML, Kim KW, Juhn JY, Hwang SY, Yoon CH, Park SH, Lee SH, Kim HY: Up-regulation of IL-23p19 expression in rheumatoid arthritis synovial fibroblasts by IL-17 through PI3-kinase-, NF-kappaB- and p38 MAPK-dependent signalling pathways. Rheumatology (Oxford). 2007, 46: 57-64. 10.1093\/rheumatology\/kel159.","journal-title":"Rheumatology (Oxford)"},{"key":"3830_CR11","first-page":"515","volume":"35","author":"S Agarwal","year":"2008","unstructured":"Agarwal S, Misra R, Aggarwal A: Interleukin 17 levels are increased in juvenile idiopathic arthritis synovial fluid and induce synovial fibroblasts to produce proinflammatory cytokines and matrix metalloproteinases. J Rheumatol. 2008, 35: 515-519.","journal-title":"J Rheumatol"},{"key":"3830_CR12","doi-asserted-by":"crossref","first-page":"597","DOI":"10.4049\/jimmunol.148.2.597","volume":"148","author":"CA Dahl","year":"1992","unstructured":"Dahl CA, Schall RP, He HL, Cairns JS: Identification of a novel gene expressed in activated natural killer cells and T cells. J Immunol. 1992, 148: 597-603.","journal-title":"J Immunol"},{"key":"3830_CR13","doi-asserted-by":"publisher","first-page":"4962","DOI":"10.1073\/pnas.1016005108","volume":"108","author":"B Heinhuis","year":"2011","unstructured":"Heinhuis B, Koenders MI, van de Loo FA, Netea MG, van den Berg WB, Joosten LA: Inflammation-dependent secretion and splicing of IL-32{gamma} in rheumatoid arthritis. Proc Natl Acad Sci USA. 2011, 108: 4962-4967. 10.1073\/pnas.1016005108.","journal-title":"Proc Natl Acad Sci USA"},{"key":"3830_CR14","doi-asserted-by":"publisher","first-page":"480","DOI":"10.1111\/j.1365-2249.2007.03439.x","volume":"149","author":"M Shioya","year":"2007","unstructured":"Shioya M, Nishida A, Yagi Y, Ogawa A, Tsujikawa T, Kim-Mitsuyama S, Takayanagi A, Shimizu N, Fujiyama Y, Andoh A: Epithelial overexpression of interleukin-32alpha in inflammatory bowel disease. Clin Exp Immunol. 2007, 149: 480-486. 10.1111\/j.1365-2249.2007.03439.x.","journal-title":"Clin Exp Immunol"},{"key":"3830_CR15","first-page":"289","volume":"16","author":"N Cagnard","year":"2005","unstructured":"Cagnard N, Letourneur F, Essabbani A, Devauchelle V, Mistou S, Rapinat A, Decraene C, Fournier C, Chiocchia G: Interleukin-32, CCL2, PF4F1 and GFD10 are the only cytokine\/chemokine genes differentially expressed by in vitro cultured rheumatoid and osteoarthritis fibroblast-like synoviocytes. Eur Cytokine Netw. 2005, 16: 289-292.","journal-title":"Eur Cytokine Netw"},{"key":"3830_CR16","doi-asserted-by":"publisher","first-page":"16309","DOI":"10.1073\/pnas.0508237102","volume":"102","author":"MG Netea","year":"2005","unstructured":"Netea MG, Azam T, Ferwerda G, Girardin SE, Walsh M, Park JS, Abraham E, Kim JM, Yoon DY, Dinarello CA, Kim SH: IL-32 synergizes with nucleotide oligomerization domain (NOD) 1 and NOD2 ligands for IL-1beta and IL-6 production through a caspase 1-dependent mechanism. Proc Natl Acad Sci USA. 2005, 102: 16309-16314. 10.1073\/pnas.0508237102.","journal-title":"Proc Natl Acad Sci USA"},{"issue":"Suppl 3","key":"3830_CR17","doi-asserted-by":"crossref","first-page":"iii61","DOI":"10.1136\/ard.2006.058511","volume":"65","author":"CA Dinarello","year":"2006","unstructured":"Dinarello CA, Kim SH: IL-32, a novel cytokine with a possible role in disease. Ann Rheum Dis. 2006, 65 (Suppl 3): iii61-64.","journal-title":"Ann Rheum Dis"},{"key":"3830_CR18","doi-asserted-by":"publisher","first-page":"3298","DOI":"10.1073\/pnas.0511233103","volume":"103","author":"LA Joosten","year":"2006","unstructured":"Joosten LA, Netea MG, Kim SH, Yoon DY, Oppers-Walgreen B, Radstake TR, Barrera P, van de Loo FA, Dinarello CA, van den Berg WB: IL-32, a proinflammatory cytokine in rheumatoid arthritis. Proc Natl Acad Sci USA. 2006, 103: 3298-3303. 10.1073\/pnas.0511233103.","journal-title":"Proc Natl Acad Sci USA"},{"key":"3830_CR19","doi-asserted-by":"publisher","first-page":"3112","DOI":"10.4049\/jimmunol.0801967","volume":"182","author":"S Zrioual","year":"2009","unstructured":"Zrioual S, Ecochard R, Tournadre A, Lenief V, Cazalis MA, Miossec P: Genome-wide comparison between IL-17A- and IL-17F-induced effects in human rheumatoid arthritis synoviocytes. J Immunol. 2009, 182: 3112-3120. 10.4049\/jimmunol.0801967.","journal-title":"J Immunol"},{"key":"3830_CR20","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1136\/ard.2010.139196","volume":"70","author":"B Heinhuis","year":"2011","unstructured":"Heinhuis B, Koenders MI, van Riel PL, van de Loo FA, Dinarello CA, Netea MG, van den Berg WB, Joosten LA: Tumour necrosis factor alpha-driven IL-32 expression in rheumatoid arthritis synovial tissue amplifies an inflammatory cascade. Ann Rheum Dis. 2011, 70: 660-667. 10.1136\/ard.2010.139196.","journal-title":"Ann Rheum Dis"},{"key":"3830_CR21","doi-asserted-by":"publisher","first-page":"6848","DOI":"10.4049\/jimmunol.1003996","volume":"186","author":"MY Jung","year":"2011","unstructured":"Jung MY, Son MH, Kim SH, Cho D, Kim TS: IL-32gamma induces the maturation of dendritic cells with Th1- and Th17-polarizing ability through enhanced IL-12 and IL-6 production. J Immunol. 2011, 186: 6848-6859. 10.4049\/jimmunol.1003996.","journal-title":"J Immunol"},{"key":"3830_CR22","doi-asserted-by":"publisher","first-page":"7127","DOI":"10.4049\/jimmunol.1002306","volume":"186","author":"E Turner-Brannen","year":"2011","unstructured":"Turner-Brannen E, Choi KY, Arsenault R, El-Gabalawy H, Napper S, Mookherjee N: Inflammatory cytokines IL-32 and IL-17 have common signaling intermediates despite differential dependence on TNF-receptor 1. J Immunol. 2011, 186: 7127-7135. 10.4049\/jimmunol.1002306.","journal-title":"J Immunol"},{"key":"3830_CR23","doi-asserted-by":"publisher","first-page":"e4173","DOI":"10.1371\/journal.pone.0004173","volume":"4","author":"G Mabilleau","year":"2009","unstructured":"Mabilleau G, Sabokbar A: Interleukin-32 promotes osteoclast differentiation but not osteoclast activation. PLoS One. 2009, 4: e4173-10.1371\/journal.pone.0004173.","journal-title":"PLoS One"},{"key":"3830_CR24","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1002\/art.27197","volume":"62","author":"YG Kim","year":"2010","unstructured":"Kim YG, Lee CK, Oh JS, Kim SH, Kim KA, Yoo B: Effect of interleukin-32gamma on differentiation of osteoclasts from CD14+ monocytes. Arthritis Rheum. 2010, 62: 515-523.","journal-title":"Arthritis Rheum"},{"key":"3830_CR25","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1089\/jir.2011.0094","volume":"31","author":"B Astry","year":"2011","unstructured":"Astry B, Harberts E, Moudgil KD: A cytokine-centric view of the pathogenesis and treatment of autoimmune arthritis. J Interferon Cytokine Res. 2011, 31: 927-940. 10.1089\/jir.2011.0094.","journal-title":"J Interferon Cytokine Res"},{"key":"3830_CR26","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1186\/ar115","volume":"2","author":"IB McInnes","year":"2000","unstructured":"McInnes IB, Leung BP, Liew FY: Cell-cell interactions in synovitis. Interactions between T lymphocytes and synovial cells. Arthritis Res. 2000, 2: 374-378. 10.1186\/ar115.","journal-title":"Arthritis Res"},{"key":"3830_CR27","doi-asserted-by":"publisher","first-page":"R135","DOI":"10.1186\/ar3073","volume":"12","author":"G Alsaleh","year":"2010","unstructured":"Alsaleh G, Sparsa L, Chatelus E, Ehlinger M, Gottenberg JE, Wachsmann D, Sibilia J: Innate immunity triggers IL-32 expression by fibroblast-like synoviocytes in rheumatoid arthritis. Arthritis Res Ther. 2010, 12: R135-10.1186\/ar3073.","journal-title":"Arthritis Res Ther"},{"key":"3830_CR28","doi-asserted-by":"publisher","first-page":"R166","DOI":"10.1186\/ar2074","volume":"8","author":"H Shoda","year":"2006","unstructured":"Shoda H, Fujio K, Yamaguchi Y, Okamoto A, Sawada T, Kochi Y, Yamamoto K: Interactions between IL-32 and tumor necrosis factor alpha contribute to the exacerbation of immune-inflammatory diseases. Arthritis Res Ther. 2006, 8: R166-10.1186\/ar2074.","journal-title":"Arthritis Res Ther"},{"key":"3830_CR29","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1002\/path.2899","volume":"224","author":"HJ Jeong","year":"2011","unstructured":"Jeong HJ, Shin SY, Oh HA, Kim MH, Cho JS, Kim HM: IL-32 up-regulation is associated with inflammatory cytokine production in allergic rhinitis. J Pathol. 2011, 224: 553-563. 10.1002\/path.2899.","journal-title":"J Pathol"},{"key":"3830_CR30","first-page":"263","volume":"27","author":"Y Yagi","year":"2011","unstructured":"Yagi Y, Andoh A, Imaeda H, Aomatsu T, Ohsaki R, Inatomi O, Bamba S, Tsujikawa T, Shimizu T, Fujiyama Y: Interleukin-32alpha expression in human colonic subepithelial myofibroblasts. Int J Mol Med. 2011, 27: 263-268.","journal-title":"Int J Mol Med"},{"key":"3830_CR31","doi-asserted-by":"publisher","first-page":"678","DOI":"10.1002\/art.24299","volume":"60","author":"SH Mun","year":"2009","unstructured":"Mun SH, Kim JW, Nah SS, Ko NY, Lee JH, Kim JD, Kim do K, Kim HS, Choi JD, Kim SH, Lee CK, Park SH, Kim BK, Kim HS, Kim YM, Choi WS: Tumor necrosis factor alpha-induced interleukin-32 is positively regulated via the Syk\/protein kinase Cdelta\/JNK pathway in rheumatoid synovial fibroblasts. Arthritis Rheum. 2009, 60: 678-685. 10.1002\/art.24299.","journal-title":"Arthritis Rheum"}],"container-title":["Arthritis Research &amp; Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/ar4089.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/ar4089\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/ar4089.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,20]],"date-time":"2025-04-20T20:18:25Z","timestamp":1745180305000},"score":1,"resource":{"primary":{"URL":"https:\/\/arthritis-research.biomedcentral.com\/articles\/10.1186\/ar4089"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,11,13]]},"references-count":31,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2012,12]]}},"alternative-id":["3830"],"URL":"https:\/\/doi.org\/10.1186\/ar4089","relation":{},"ISSN":["1478-6354"],"issn-type":[{"value":"1478-6354","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,11,13]]},"assertion":[{"value":"20 June 2012","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 July 2012","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 October 2012","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 November 2012","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"R246"}}