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: Mark N Polizzotto, Thomas S Uldrick, Victoria Wang, Karen Aleman, Kathleen M Wyvill, Vickie Marshall, Stefania Pittaluga, Deirdre O'Mahony, Denise Whitby, Giovanna Tosato, Seth M Steinberg, Richard F Little, Robert Yarchoan
• Journal: Blood (Blood) Vol. 122 Issue 26 Pg. 4189-98 (Dec 19 2013) ISSN: 1528-0020 [Electronic] United States
• PMID: 24174627 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• CXCL8 protein, human
• Cytokines
• IL10 protein, human
• IL6 protein, human
• Interleukin-1beta
• Interleukin-6
• Interleukin-8
• Tumor Necrosis Factor-alpha
• Interleukin-10
• Interleukin-12
• Interferon-gamma

Topics

• Adult
• Castleman Disease (etiology, immunology)
• Cytokines (immunology, metabolism)
• Female
• Herpesvirus 8, Human (immunology)
• Humans
• Interferon-gamma (immunology, metabolism)
• Interleukin-10 (immunology, metabolism)
• Interleukin-12 (immunology, metabolism)
• Interleukin-1beta (immunology, metabolism)
• Interleukin-6 (immunology, metabolism)
• Interleukin-8 (immunology, metabolism)
• Male
• Middle Aged
• Prospective Studies
• Sarcoma, Kaposi (complications, immunology)
• Tumor Necrosis Factor-alpha (immunology, metabolism)