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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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“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]
In the citing paper
“Generally, surgical removal of hyperplastic lymph nodes results in symptomatic improvement and reduced serum IL-6 concentrations (Yoshizaki et al., 1989”
From Targeting Interleukin-6 Signaling in Clinic (2019) · cites this paper as Yoshizaki et al., 1989
Citations
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“In an early study, the production of IL-6 by blastoid B cells in the germinal center of affected lymph nodes was identified, and the clinical and biological abnormalities including an elevated level of serum IL-6, which normalized after lymph node excision [19].”
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“IL-6 drives B-cell proliferation and permanent differentiation into mature immunoglobulin-producing plasma cells (9).”
BackgroundCastleman’s Disease of the Neck: Report of Four Cases with Unusual Presentations
Jiang, L., Zhao, L.-Y., Liu, Y., & Zhao, Y.-F. (2010) · Journal of oral and maxillofacial surgery · doi:10.1016/j.joms.2010.03.007 · Cited by 19
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“The serum IL-6 level has also been reported to be an autocrine growth factor in lymphoma cell lines [38].”
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“…cells No. 1 0.404 {0.03} 29.865 {0.60} No. 2 1.249 {0.04} 42.697 {1.17} a ng/ml; mean {SE} b Value for supernatant of FDC/dividing cells, previously activated with 20 ng/ml rh IL-4+100 U/ml rh γ-IFN c ND, Not detectable&/tbl.b: duced by FDC (Yoshizaki et al. 1989; Leger-Ravet et al. 1991).”
InfluentialControl of Listeria monocytogenes infection requires classical IL-6 signaling in myeloid cells
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“IL-6 is also highly expressed in germinal centers in patients with Castleman’s disease, a type of lymphoproliferative disorder (41).”
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“disease as rheumatoid arthritis (RA) [51,52], juvenile idiopathic arthritis (JIA) [53], adultonset Still’s disease (AOSD) [54], giant cell arteritis (GCA) [55] and Castleman disease [56], cytokine release syndrome, and uveitis [19].”
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“Children with Castleman’s disease require a TCZ dosage of 8 mg/kg weekly because in this systemic diseaselymphocytes and macrophages of the affected lymph nodes continuously produce IL-6 [23,24].”
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Novel Small Molecule Inhibitors Targeting the IL-6/STAT3 Pathway or IL-1β
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“Among these cytokines, RA is characterized by systemic inflammation with elevated levels of serum IL-6 [10,11].”
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“Serum IL-6 and CRP concentrations drop rapidly after resection of lymphadenopathy in patients with unicentric Castleman disease, which brings relief of its clinical symptoms [20].”
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“(%) 1/2 (50) 1/2 (50) 0/1 (0) IL-6, pg/mL, median (range) <10 (<5 to 15) 41 (5-77) <10 (<10)”
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A rare case of hyaline-type Castleman disease in the liver.
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Interfollicular Hodgkin's lymphoma and Castleman's disease
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“For example, CD209 (DC-SIGN) seems to be unsuitable for in situ staining, whereas few data have been reported for immunohistochemistry with CD80, CD86 and CD11c on paraffin sections.(2,3)”
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“However, there have been no previous reports supporting this possibility and only IL-6 has previously been detected in patient sera or in LN culture supernatant (5).”
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“Immunohistochemical and gene expression studies revealed increased IL-6 production in affected lymph nodes in patients with localized Castleman's disease (2, 10).”
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“These viruses may lead to the oversecretion of inflammatory mediators, particularly interleukin‑6 (21,22), which results in the induction of a hyperplasic reaction of the lymphoid system.”
Multicentric Castleman disease presenting with fever.
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“IL-6 is produced by B lymphocytes within the germinal centers of hyperplastic lymph nodes; in unicentric CD, IL-6 levels fall after the affected lymph node is resected.(16,17) HHV-8 has been linked to CD, especially in adults with HIV infection, and its genome harbors a viral analog of IL-6.”
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“On the other hand, elevated expression of interleukin-6 (IL-6) is considered to be related to the pathogenesis of the plasma cell type, explaining above-mentioned symptoms [6].”
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“It has been reported recently the interleukin (IL)-6 is involved in the mechanism of clinical manifestation.(25,26) HHV-8 encodes a gene product that is homolog of human IL-6 (vIL-6),(27) and it is thought to be responsible for the clinical symptoms.”
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Bottieau, E., Colebunders, R., Schroyens, W., Droogenbroeck, J. V. V., de Droogh, E., Depraetere, K., de Raeve, H., & Marck, E. V. V. (2000) · Acta Clinica Belgica · doi:10.1080/17843286.2000.11754278 · Cited by 14
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BackgroundSerum Levels of Interleukin 6 in Patients with Pustulosis Palmaris et Plantaris
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“IL6 induces differentiation of B cells into plasma cells and promotes vascular growth via expression of vascular endothelial growth factors [2].”
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“The key role of interleukin-6 (IL-6) production in the development of MCD is emphasized (Talat et al. 2012; Yoshizaki et al. 1989).”
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“Renal biopsy revealed glomerular basement membrane abnormalities and endocapillary proliferation, suggestive of thrombotic microangiopathy, which has been previously described in MCD [9,10,11].”
BackgroundInfluentialHirano, H., Yoshioka, T., Yunoue, S., Fujio, S., Yonezawa, H., Niiro, T., Habu, M., Oyoshi, T., Sugata, S., Kamezawa, T., et al. (2012) · Neuropathology · doi:10.1111/j.1440-1789.2012.01310.x · Cited by 13
“In the pathogenesis of Castleman’s disease, IL-6 is a pivotal cytokine.(16) In multicentric Castleman’s disease, there are cases in which many plasma cells express IgG4.”
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2 ‐Chloro‐deoxyadenosine therapy for giant lymph node hyperplasia
Bordeleau, L., Bredeson, C., & Markman, S. (1995) · British Journal of Haematology · doi:10.1111/j.1365-2141.1995.tb05366.x · Cited by 13
“the latter being felt by some to be responsible for the systemic manifestations of GLNH (Yoshikazi et al. 1989).”
BackgroundMulticentric Castleman's disease in a patient with primary Sjögren's syndrome
Tavoni, A., Vitali, C., Baglioni, P., Gerli, R., Marchetti, G., Munno, O., & Bombardieri, S. (1992) · Rheumatology International · doi:10.1007/bf00301012 · Cited by 13
“been found both in Castleman's disease [18] and in SS [19]”
BackgroundBelyaeva, E., Rubenstein, A., Pierson, S., Dalldorf, D., Frank, D. M., Lim, M., & Fajgenbaum, D. (2022) · Hematological Oncology · doi:10.1002/hon.2969 · Cited by 12
“Clinical symptoms and disease pathogenesis are driven by excessive cytokines, often including Interleukin‐6 (IL‐6).(2,3) There are currently three recognized subtypes.”
BackgroundClassic Hodgkin lymphoma and Castleman disease: an entity appears to be emerging
Lyapichev, K. A., You, M., Vega, F., Solis, L., & Medeiros, L. (2020) · Virchows Archiv · doi:10.1007/s00428-020-02788-7 · Cited by 12
A rare case of renal thrombotic microangiopathy associated with Castleman’s disease
Mutneja, A., Cossey, L., Liapis, H., & Chen, Y. (2017) · BMC Nephrology · doi:10.1186/s12882-017-0472-2 · Cited by 12
“Proliferating plasma cells in lymph nodes cause overproduction of both cytokines leading to elevated systemic levels [11, 12].”
BackgroundHerpesvirus infections of laboratory macaques
Simmons, J. (2010) · Journal of Immunotoxicology · doi:10.3109/15476910903409843 · Cited by 12
“Castleman’s disease is associated with increased interleukin (IL)-6 expression, is commonly seen in immune suppressed KSHV-infected humans, and KSHV DNA sequences have been associated with CD lesions (Yoshizaki et al., 1989; Brandt et al., 1990; Soulier et al., 1995; Ganem, 2007).”
BackgroundSadamoto, Y., Abe, Y., Higuchi, K., Kato, K., Matsumoto, S., Arima, N., & Nawata, H. (1998) · Internal medicine · doi:10.2169/internalmedicine.37.691 · Cited by 12
Pannuti, C. M., Gingrich, R., Pfaller, M. A., kao, C., & Wenzel, R. P. (1992) · Cancer · doi:10.1002/1097-0142(19920601)69:11 · Cited by 116
Loss of interleukin-21 leads to atrophic germinal centers in multicentric Castleman’s disease
Yajima, H., Yamamoto, M., Shimizu, Y., Sakurai, N., Suzuki, C., Naishiro, Y., Imai, K., Shinomura, Y., & Takahashi, H. (2015) · Annals of Hematology · doi:10.1007/s00277-015-2500-2 · Cited by 12
“The pathogenesis of MCD remains unknown, but overproduction of IL-6 and other cytokines is suggested to be involved [8].”
BackgroundEpstein-Barr Virus and Human Cancer
Takada, K. (2012) · Current Topics in Microbiology and Immunology · doi:10.1007/978-3-642-56515-1 · Cited by 11
The Characterization and Management of Castleman's Disease
Zhou, N., Huang, C.-W., Huang, C., & Liao, W. (2012) · Journal of International Medical Research · doi:10.1177/147323001204000438 · Cited by 11
Deshmukh, M., Bal, M., Deshpande, P., & Jambhekar, N. (2011) · Head and Neck Pathology · doi:10.1007/s12105-011-0240-8 · Cited by 11
“A key event in the pathogenesis of CD has been recently suggested to be an abnormal production of a B cell growth factor, such as IL-6, leading to lymphoid cell proliferation and plasma cell differentiation [3, 4].”
BackgroundHypophosphatemia in juvenile patients with systemic lupus erythematosus
Fujiwara, I., Ogawa, E., Kondo, Y., Ohura, T., & Iinuma, K. (2003) · Pediatrics International · doi:10.1046/j.1442-200x.2003.01665.x · Cited by 11
Moss, S. F., Thomas, D., Mulnier, C., McGill, I. G., & Hodgson, H. (1992) · Gut · doi:10.1136/gut.33.1.135 · Cited by 11
Piattini, F., Sidiropoulos, N. D., Berest, I., & Köpf, M. (2025) · Mucosal Immunology · doi:10.1016/j.mucimm.2025.02.001 · Cited by 13
Sumiyoshi, R., Koga, T., & Kawakami, A. (2024) · Biomedicines · doi:10.3390/biomedicines12061141 · Cited by 10
“The disease is characterized by the widespread proliferation of lymphocytes and a significant increase in cytokines, particularly IL-6 [6–8].”
BackgroundFurutera, N., Fukunaga, N., Okita, J., Suzuki, T., Suenaga, Y., Oyama, Y., Aoki, K., Fukuda, A., Nakata, T., Uesugi, N., et al. (2020) · CEN Case Reports · doi:10.1007/s13730-020-00511-8 · Cited by 10
Treatment response and prognosis of POEMS syndrome coexisting with Castleman disease.
Suichi, T., Misawa, S., Sekiguchi, Y., Shibuya, K., Tsuneyama, A., Suzuki, Y.-I., Nakamura, K., Kano, H., & Kuwabara, S. (2020) · Journal of Neurological Sciences · doi:10.1016/j.jns.2020.116771 · Cited by 10
AA amyloidosis associated with Castleman disease
Bernabei, L., Waxman, A., Caponetti, G., Fajgenbaum, D., & Weiss, B. (2020) · Medicine · doi:10.1097/md.0000000000018978 · Cited by 10
Furuto, Y., Hashimoto, H., Horiuti, H., & Shibuya, Y. (2018) · Medicine · doi:10.1097/md.0000000000011057 · Cited by 10
Maxillary Sinus Inflammatory Myofibroblastic Tumors: A Review and Case Report
Hansen, C., Eisenbach, C., Torres, C., Graham, S., & Hardwicke, F. (2015) · Case Reports in Oncological Medicine · doi:10.1155/2015/953857 · Cited by 10
“dysregulation play in the survival and growth of these lesions [20, 33–35, 60, 61].”
BackgroundUnicentric mixed variant Castleman disease associated with intrabronchial plasmacytoma
Eszes, N., Tamási, L., Csekeő, A., Csomor, J., Szepesi, Á., Varga, G., Balázs, G., Losonczy, G., & Müller, V. (2014) · Diagnostic Pathology · doi:10.1186/1746-1596-9-64 · Cited by 10
“The role of IL-6 cytokine may be one of the key components in the pathophysiology of the disease, its overexpression in germinal center cells of the lymph nodes was shown in the plasma cell type of CD [24].”
BackgroundReversal of cardiomyopathy with tocilizumab in a case of HIV‐negative Castleman's disease
Man, L., & Goudar, R. K. (2013) · European Journal of Haematology · doi:10.1111/ejh.12161 · Cited by 10
“IL-6 is a critical B-cell proliferation signal and is important in lymph node hyperplasia in CD (23, 24); most CD patients have elevated serum levels of IL-6, and HHV-8 has been shown to produce a human IL-6 homologue (24, 25).”
BackgroundCastleman Disease in the Parapharyngeal Space: A Case Report and Review of the Literature
Clain, J. B., Scherl, S., Karle, W. E., Khorsandi, A., Ghali, V., Wang, B., & Urken, M. (2013) · Head and Neck Pathology · doi:10.1007/s12105-013-0449-9 · Cited by 10
“in 1989 [15–17].”
Park, H., Lee, J., Lee, J., Kim, S.-J., Lee, S.-C., Won, Y., & Yun, S. (2011) · Annals of Dermatology · doi:10.5021/ad.2011.23.s2.s169 · Cited by 10
“Yoshizaki et al.20 showed that the cells present in the germinal center of the enlarged lymph nodes produce IL-6 and there is close relationship between the serum levels of IL-6 and the clinical symptoms of patients with CD. Recently, the incidence of CD in HIV patients has increased10.”
Background
Metadata
- 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 › Pathology and Forensic Medicine › 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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