Human and viral interleukin-6 and other cytokines in Kaposi sarcoma herpesvirus-associated multicentric Castleman disease

Polizzotto, Mark N.; Uldrick, Thomas S.; Wang, Victoria; Aleman, Karen; Wyvill, Kathleen M.; Marshall, Vickie; Pittaluga, Stefania; O’Mahony, Deirdre; Whitby, Denise; Tosato, Giovanna; Steinberg, Seth M.; Little, Richard F.; Yarchoan, Robert

doi:10.1182/blood-2013-08-519959

Cited by 134 publications

(131 citation statements)

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“…45 The number of cellular equivalents was determined using a human endogenous retrovirus 3 PCR assay. 47 Serum vIL-6 was measured using a sandwich enzyme-linked immunosorbent assay 3,17 that does not crossreact with human IL-6 at concentrations up to 10 000 pg/mL. 3,17 The lower limit of detection of vIL-6 was 1560 pg/mL.…”

Section: Kshv Viral Load and Serum Viral Il-6mentioning

confidence: 99%

“…Symptomatic patients generally have elevated C-reactive protein (CRP) and KSHV viral load, and they often have anemia, thrombocytopenia, hypoalbuminemia, hyponatremia, and elevated g-globulin. [2][3][4][5][6][7][8][9] Computerized tomography (CT) typically demonstrates diffuse adenopathy and splenomegaly. Diagnosis requires pathologic confirmation.…”

Section: Introductionmentioning

confidence: 99%

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Rituximab plus liposomal doxorubicin in HIV-infected patients with KSHV-associated multicentric Castleman disease

Uldrick

Polizzotto

Aleman

et al. 2014

Blood

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101

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Section: Kshv Viral Load and Serum Viral Il-6mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Rituximab plus liposomal doxorubicin in HIV-infected patients with KSHV-associated multicentric Castleman disease

Uldrick

Polizzotto

Aleman

et al. 2014

Blood

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101

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“…temic vIL-6 proteins are important contributors to the pathogenesis and symptomatology of KSHV-MCD (24)(25)(26)(27). KSHV-MCD flares are characterized by systemic expression of vIL-6 and/or hIL-6 (24,25,28,29).…”

mentioning

confidence: 99%

Induction of Kaposi's Sarcoma-Associated Herpesvirus-Encoded Viral Interleukin-6 by X-Box Binding Protein 1

Wang

Yang

et al. 2016

J Virol

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Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent for Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and a subset of multicentric Castleman disease (MCD). The KSHV life cycle has two principal gene repertoires, latent and lytic. KSHV viral interleukin-6 (vIL-6), an analog of human IL-6, is usually lytic; production of vIL-6 by involved plasmablasts is a central feature of KSHV-MCD. vIL-6 also plays a role in PEL and KS. We show that a number of plasmablasts from lymph nodes of patients with KSHV-MCD express vIL-6 but not ORF45, a KSHV lytic gene. We further show that vIL-6 is directly induced by the spliced (active) X-box binding protein-1 (XBP-1s), a transcription factor activated by endoplasmic reticulum (ER) stress and differentiation of B cells in lymph nodes. The promoter region of vIL-6 contains several potential XBP-response elements (XREs), and two of these elements in particular mediate the effect of XBP-1s. Mutation of these elements abrogates the response to XBP-1s but not to the KSHV replication and transcription activator (RTA). Also, XBP-1s binds to the vIL-6 promoter in the region of these XREs. Exposure of PEL cells to a chemical inducer of XBP-1s can induce vIL-6. Patient-derived PEL tumor cells that produce vIL-6 frequently coexpress XBP-1, and immunofluorescence staining of involved KSHV-MCD lymph nodes reveals that most plasmablasts expressing vIL-6 also coexpress XBP-1. These results provide evidence that XBP-1s is a direct activator of KSHV vIL-6 and that this is an important step in the pathogenesis of KSHV-MCD and PEL. IMPORTANCE Kaposi sarcoma herpesvirus (KSHV)-associated multicentric Castleman disease (KSHV-MCD)is characterized by severe inflammatory symptoms caused by an excess of cytokines, particularly KSHV-encoded viral interleukin-6 (vIL-6) produced by lymph node plasmablasts. vIL-6 is usually a lytic gene. We show that a number of KSHV-MCD lymph node plasmablasts express vIL-6 but do not have full lytic KSHV replication. Differentiating lymph node B cells express spliced (active) X-box binding protein-1 (XBP-1s). We show that XBP-1s binds to the promoter of vIL-6 and can directly induce production of vIL-6 through X-box protein response elements on the vIL-6 promoter region. We further show that chemical inducers of XBP-1s can upregulate production of vIL-6. Finally, we show that most vIL-6-producing plasmablasts from lymph nodes of KSHV-MCD patients coexpress XBP-1s. These results demonstrate that XBP-1s can directly induce vIL-6 and provide evidence that this is a key step in the pathogenesis of KSHV-MCD and other KSHV-induced diseases.

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“…[29] The pathogenesis of Castleman disease is not fully understood; however, the central roles of interleukin (IL) 6 in UCD and both IL-6 and human herpesvirus (HHV) 8 in MCD have been well described. [30,31] Dysregulated and overproduced IL-6, particularly in patients with MCD, stimulates the production of acute phase reactants in the liver, resulting in constitutional symptoms, including fever, sweats, and fatigue, and laboratory abnormalities, such as anemia, elevated inflammatory markers, hypergammaglobulinemia, and hypoalbuminemia IL-6 also stimulates B-cell proliferation and induces the expression of vascular endothelial growth factor and increased angiogenesis. IL-6 has emerged as a therapeutic target in Castleman disease based on its critical role in pathogenesis and driving of symptomatology.…”

Section: Introductionmentioning

confidence: 99%

Association of Chronic HBV Infection with Chronic Lymphoproliferative Disorders: A Review and Case Report

Sleptsovа¹,

Yadrichinskaya²,

Palchina³

et al. 2016

Int J Biomed

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This article presents a clinical report on the associated course of chronic hepatitis B virus (HBV) infection with Castleman's disease (CD). We noticed the reactivation of previously latent chronic hepatitis B (CHB) with high replicative activity of HBV DNA during the treatment of lymphoproliferative disease. This clinical case dictates the need for pre-emptive therapy of HBV infection with nucleoside analogues in patients who are receiving chemotherapy. (Int J Biomed. 2016;6(2):128-132.).

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Human and viral interleukin-6 and other cytokines in Kaposi sarcoma herpesvirus-associated multicentric Castleman disease

Abstract: Key Points Human IL-6 and a viral IL-6 homolog encoded by KSHV/HHV8 can independently or together lead to flares of KSHV-associated MCD. KSHV-MCD disease flares were more severe where both human and viral IL-6 were elevated, suggesting they jointly contribute to severity.

Cited by 134 publications

References 54 publications

Rituximab plus liposomal doxorubicin in HIV-infected patients with KSHV-associated multicentric Castleman disease

Rituximab plus liposomal doxorubicin in HIV-infected patients with KSHV-associated multicentric Castleman disease

Induction of Kaposi's Sarcoma-Associated Herpesvirus-Encoded Viral Interleukin-6 by X-Box Binding Protein 1

Association of Chronic HBV Infection with Chronic Lymphoproliferative Disorders: A Review and Case Report

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