Pathogenic significance of interleukin-6 (IL-6/BSF-2) in Castleman’s disease
Abstract
Castleman's disease is a syndrome consisting of giant lymph node hyperplasia with plasma cell infiltration, fever, anemia, hypergammaglobulinemia, and an increase in the plasma level of acute phase proteins. It has been reported that clinical abnormalities disappear after the resection of the affected lymph nodes, suggesting that products of lymph nodes may cause such clinical abnormalities. Interleukin-6 (IL-6) is a cytokine inducing B-cell differentiation to immunoglobulin-producing cells and regulating biosynthesis of acute phase proteins. This report demonstrates that the germinal centers of hyperplastic lymph nodes of patients with Castleman's disease produce large quantities of IL-6 without any significant production of other cytokines. In a patient with a solitary hyperplastic lymph node, clinical improvement and decrease in serum IL-6 were observed following surgical removal of the involved lymph node. There was a correlation between serum IL-6 level, lymph node hyperplasia, hypergammaglobulinemia, increased level of acute phase proteins, and clinical abnormalities. The findings in this report indicate that the generation of IL-6 by B cells in germinal centers of hyperplastic lymph nodes of Castleman's disease may be the key element responsible for the variety of clinical symptoms in this disease.
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IL-6 is produced by cardiac myxoma cells and Castleman's germinal center cells.
“Studies in the 1980s also showed that IL-6 is produced by cardiac myxoma cells (42) and Castleman’s germinal center cells (43)”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [43]
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“Constitutive production of IL-6 by B cells in the germinal centers of the affected lymph nodes is associated with increased IL-6 serum levels [23].”
BackgroundThe role of the interleukin (IL)-6/IL-6 receptor axis in cancer.
Taher, M. Y., Davies, D., & Maher, J. (2018) · Biochemical Society Transactions · doi:10.1042/bst20180136 · Cited by 115 · see citing works
Prognostic value of serum interleukin-6 in diffuse large-cell lymphoma
Preti, H. A., Cabanillas, F., Talpaz, M., Tucker, S. L., Seymour, J. F., & Kurzrock, R. (1997) · Annals of Internal Medicine · doi:10.7326/0003-4819-127-3-199708010-00002 · Cited by 112 · see citing works
“Interleukin-6 has also been implicated in the pathogenesis of several lymphoproliferative disorders, including multiple myeloma, lymphoma, and Castleman disease (4-14), and it may be a prognostic factor for solid tumors, such as renal cell (15), epithelial ovarian (16), and prostate cancer (17).”
BackgroundBoss, I. W., Nadeau, P. E., Abbott, J. R., Yang, Y., Mergia, A., & Renne, R. (2011) · Journal of Virology · doi:10.1128/jvi.05558-11 · Cited by 123 · see citing works
“Previous studies have shown that miR-155 can directly target and repress reporter constructs containing portions of the C/EBP 3 UTR with the miR-155 binding site (9, 36, 57).”
BackgroundMolecular analysis of clonality in Castleman's disease.
Soulier, J., Grollet, L., Oksenhendler, E., Miclea, J., Cacoub, P., Baruchel, A., Brice, P., Clauvel, J., d'Agay, M., Raphael, M., et al. (1995) · Blood · doi:10.1182/blood.v86.3.1131.1131 · Cited by 112
Update and new approaches in the treatment of Castleman disease
Chan, K.-L., Lade, S., Prince, H., & Harrison, S. (2016) · Journal of Blood Medicine · doi:10.2147/jbm.s60514 · Cited by 109
“The pathogenic contribution of IL-6 One of the earliest links between IL-6 and CD was the demonstration that the site of excess IL-6 production in CD patients was within the germinal centers of involved lymph nodes.(22) Following lymph node resection in a patient with UCD, there was a correlation between the reduction…”
Nishi, J.-I., Arimura, K., Utsunomiya, A., Yonezawa, S., Kawakami, K., Maeno, N., Ijichi, O., Ikarimoto, N., Nakata, M., Kitajima, I., et al. (1999) · British Journal of Haematology · doi:10.1046/j.1365-2141.1999.01208.x · Cited by 109 · see citing works
“…IL-6 and tumour necrosis factor (TNF)-b are thought to be associated with the variety of clinical symptoms in this disease (Gherardi et al, 1994; Yoshizaki et al, 1989; Winter et al, British Journal of Haematology, 1999, 104, 482–485 482 q 1999 Blackwell Science Ltd Correspondence: Dr…”
BackgroundKojima, M., Nakamura, N., Tsukamoto, N., Otuski, Y., Shimizu, K., Itoh, H., Kobayashi, S., Kobayashi, H., Murase, T., Masawa, N., et al. (2008) · International Journal of Surgical Pathology · doi:10.1177/1066896908315812 · Cited by 104 · see citing works
Katsarou, A., & Pantopoulos, K. (2018) · Pharmaceuticals · doi:10.3390/ph11040127 · Cited by 115 · see citing works
“Castleman disease patients present with iron-refractory hypochromic microcytic anemia, which develops in response to IL-6-mediated upregulation of hepcidin [41].”
BackgroundParaneoplastic syndromes secondary to neuroendocrine tumours
Kaltsas, G., Androulakis, I. I., de Herder, W. W., & Grossman, A. B. (2010) · Endocrine Related Cancer · doi:10.1677/erc-10-0024 · Cited by 114 · see citing works
“A PNS presenting with fever and increased acute phase proteins has been shown to be associated with elevated IL-6 levels (Dawson & Harding 1982, Yoshizaki et al. 1989, Fukumoto et al. 1991) and related tumours to secrete IL-6 (Tabibzadeh et al. 1989, Fukumoto et al. 1991).”
BackgroundIs TAFRO syndrome a subtype of idiopathic multicentric Castleman disease?
Fujimoto, S., Sakai, T., Kawabata, H., Kurose, N., Yamada, S., Takai, K., Aoki, S., Kuroda, J., Ide, M., Setoguchi, K., et al. (2019) · American journal of hematology/oncology · doi:10.1002/ajh.25554 · Cited by 99 · see citing works
“IL-6 (pg/mL) 21 (10-42) (n = 76) 26 (15-40) (n = 52) 23 (13-40) (n = 12) >.”
InfluentialTocilizumab for the treatment of rheumatoid arthritis
Tanaka, T., Ogata, A., & Narazaki, M. (2010) · Expert Review of Clinical Immunology · doi:10.1586/eci.10.70 · Cited by 99 · see citing works
Casper, C., Chaturvedi, S., Munshi, N., Wong, R., Qi, M., Schaffer, M., Bandekar, R., Hall, B., van de Velde, H., Vermeulen, J., et al. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-0134 · Cited by 97 · see citing works
Recent advances in Kaposi sarcoma herpesvirus-associated multicentric Castleman disease
Uldrick, T., Polizzotto, M., & Yarchoan, R. (2012) · Current Opinion in Oncology · doi:10.1097/cco.0b013e328355e0f3 · Cited by 97 · see citing works
Interleukin-6 as a Potential Therapeutic Target for Pulmonary Arterial Hypertension
Furuya, Y., Satoh, T., & Kuwana, M. (2010) · International Journal of Rheumatology · doi:10.1155/2010/720305 · Cited by 97 · see citing works
“The etiology of the disease appears to be heterogeneous, but dysregulated overproduction of IL-6 is believed to be responsible for the clinical abnormalities [12].”
BackgroundMethodModulation of Host Gene Expression by the K15 Protein of Kaposi's Sarcoma-Associated Herpesvirus
Brinkmann, M. M., Pietrek, M., Dittrich‐Breiholz, O., Kracht, M., & Schulz, T. F. (2006) · Journal of Virology · doi:10.1128/jvi.00648-06 · Cited by 83 · see citing works
“IL-6 is expressed in KSHV-associated tumors (5, 30, 31, 68, 77, 89, 131, 133) and is highly upregulated and escapes the viral host gene expression shutoff mediated by the KSHV-encoded shutoff exonuclease (ORF37) during lytic KSHV growth (42, 43).”
BackgroundRenal involvement in Castleman disease.
Karoui, K. E., Vuiblet, V., Dion, D., Izzedine, H., Guitard, J., Frimat, L., Delahousse, M., Rémy, P., Boffa, J., Pillebout, É., et al. (2011) · Nephrology, Dialysis and Transplantation · doi:10.1093/ndt/gfq427 · Cited by 95
“Symptoms of CD have also been correlated with serum IL-6 levels in humans [22].”
BackgroundAnti-interleukin-6 receptor antibody (tocilizumab) treatment of multicentric Castleman's disease.
Matsuyama, M., Suzuki, T., Tsuboi, H., Ito, S., Mamura, M., Goto, D., Matsumoto, I., Tsutsumi, A., & Sumida, T. (2007) · Internal medicine · doi:10.2169/internalmedicine.46.6262 · Cited by 94 · see citing works
“Overproduction of IL-6 by germinal center B cells is implicated in the pathogenesis of MCD (2, 3).”
BackgroundThe immune system in aging: roles of cytokines, T cells and NK cells
Huang, H. W. (2005) · Frontiers in bioscience · doi:10.2741/1521 · Cited by 98 · see citing works
Kojima, M., Nakamura, S., Morishita, Y., Itoh, H., Yoshida, K., Ohno, Y., Oyama, T., Asano, S., Joshita, T., Mori, S., et al. (2000) · Pathology international (Print) · doi:10.1046/j.1440-1827.2000.01052.x · Cited by 92 · see citing works
Chadburn, A., Hyjek, E., Tam, W., Liu, Y.-F., Rengifo, T., Cesarman, E., & Knowles, D. (2008) · Histopathology · doi:10.1111/j.1365-2559.2008.03144.x · Cited by 91 · see citing works
Rieckmann, P., Poli, G., Kehrl, J., & Fauci, A. (1991) · Journal of Experimental Medicine · doi:10.1084/jem.173.1.1 · Cited by 91
Plasma proteomics identifies a ‘chemokine storm’ in idiopathic multicentric Castleman disease
Pierson, S. K., Stonestrom, A. J., Shilling, D., Ruth, J., Nabel, C. S., Singh, A., Ren, Y., Stone, K., Li, H., van Rhee, F., et al. (2018) · American Journal of Hematology · doi:10.1002/ajh.25123 · Cited by 90 · see citing works
“Several lines of evidence suggest that excess interleukin-6 (IL-6), a cytokine that promotes B cell and plasma cell growth, plays an important role in symptoms and disease progression in many iMCD patients.(11,12) Anti-IL-6 monoclonal antibodies (mAb) tocilizumab (antiIL-6 receptor) and siltuximab (anti-IL-6) have bee…”
BackgroundSugita, T., Totsuka, T., Saito, M., Yamasaki, K., Taga, T., Hirano, T., & Kishimoto, T. (1990) · Journal of Experimental Medicine · doi:10.1084/jem.171.6.2001 · Cited by 90 · see citing works
Ocio, E., Sanchez-Guijo, F., Díez-Campelo, M., Castilla, C., Blanco, O., Caballero, D., & Miguel, J. S. S. (2005) · American journal of hematology/oncology · doi:10.1002/ajh.20283 · Cited by 88 · see citing works
- Authors
- Yoshizaki, K., Matsuda, T., Nishimoto, N., Kuritani, T., Taeho, L., Aozasa, K., Nakahata, T., Kawai, H., Tagoh, H., & Komori, T.
- Affiliations
- The University of Osaka (JP)
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 1989-09-01
- Volume
- 74
- Issue
- 4
- Pages
- 1360-1367
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W1632068222
- Cited by
- 928
- References
- 0
- Citations by year
- 2026: 11 · 2025: 27 · 2024: 23 · 2023: 15 · 2022: 29 · 2021: 20 · 2020: 32 · 2019: 18 · 2018: 33 · 2017: 37 · 2016: 21 · 2015: 38 · 2014: 35 · 2013: 34 · 2012: 25
- FWCI
- 14.01
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Viral-associated cancers and disorders
- Health Sciences › Medicine › Surgery › Lymphadenopathy Diagnosis and Analysis
- Health Sciences › Medicine › Hematology › Autoimmune and Inflammatory Disorders Research
- Keywords
- Castleman disease, interleukin-6, germinal center, B cells, lymph node hyperplasia, hypergammaglobulinemia, acute phase proteins, plasma cell infiltration, surgical resection, cytokine production
- MeSH terms
- Adolescent, Female, Castleman Disease, Humans, Interleukins, Lymph Node Excision, Lymph Nodes, Lymphatic Diseases, Middle Aged, Interleukin-6
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