title: Human and viral interleukin-6 and other cytokines in Kaposi sarcoma herpesvirus-associated multicentric Castleman disease.
abstract: Kaposi sarcoma herpesvirus (KSHV)-associated multicentric Castleman disease (MCD) is a polyclonal B-cell lymphoproliferative disorder. Human (h) IL-6 and a KSHV-encoded homolog, viral IL-6, have been hypothesized to contribute to its pathogenesis, but their relative contributions to disease activity is not well understood. We prospectively characterized KSHV viral load (VL), viral (v) and hIL-6, and other cytokines during KSHV-MCD flare and remission in 21 patients with 34 flares and 20 remissions. KSHV-VL, vIL-6, hIL-6, IL-10, and to a lesser extent TNF-α, and IL-1β were each elevated during initial flares compared with remission. Flares fell into 3 distinct IL-6 profiles: those associated with elevations of vIL6-only (2 flares, 6%), hIL-6 elevations only (17 flares, 50%), and elevations in both hIL-6 and vIL-6 (13 flares, 38%). Compared with hIL-6-only flares, flares with elevated hIL-6 plus vIL-6 exhibited higher C-reactive protein (CRP) (P = .0009); worse hyponatremia (P = .02); higher KSHV VL (P = .016), and higher IL-10 (P = .012). This analysis shows vIL-6 and hIL-6 can independently or together lead to KSHV-MCD flares, and suggests that vIL-6 and hIL-6 may jointly contribute to disease severity. These findings have implications for the development of novel KSHV-MCD therapies targeting IL-6 and its downstream signaling. This trial was registered at clinicaltrials.gov as #NCT099073.
authors.affiliation: HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD;
authors.forename: Mark N
authors.initials: MN
authors.lastname: Polizzotto
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Uldrick
authors.forename: Victoria
authors.initials: V
authors.lastname: Wang
authors.forename: Karen
authors.initials: K
authors.lastname: Aleman
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Wyvill
authors.forename: Vickie
authors.initials: V
authors.lastname: Marshall
authors.forename: Stefania
authors.initials: S
authors.lastname: Pittaluga
authors.forename: Deirdre
authors.initials: D
authors.lastname: O'Mahony
authors.forename: Denise
authors.initials: D
authors.lastname: Whitby
authors.forename: Giovanna
authors.initials: G
authors.lastname: Tosato
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: Richard F
authors.initials: RF
authors.lastname: Little
authors.forename: Robert
authors.initials: R
authors.lastname: Yarchoan
mesh_terms: D000328:Adult; D005871:Castleman Disease / Q000209:etiology / Q000276:immunology*; D016207:Cytokines / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D019288:Herpesvirus 8, Human / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D016209:Interleukin-8 / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012514:Sarcoma, Kaposi / Q000150:complications / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
chemical_list: C508606:CXCL8 protein, human; D016207:Cytokines; C508609:IL10 protein, human; C508600:IL6 protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma