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.

Trial registration: ClinicalTrials.gov NCT00092222 NCT00099073 NCT00092222.

Figure 1

KSHV VLs, vIL-6, and human cytokines in relation to KSHV-MCD disease activity. KSHV VL, vIL-6, and several human cytokines differ significantly between KSHV-MCD flare and remission. Statistical comparisons were made between initial flare and remission. Values are log transformed; units for all human cytokines and for vIL-6 are pg/mL and for KSHV VL is copies/10⁶ PBMCs. For IL-6 and TNF-α, the midpoint of levels found in 9 to 10 normal donors using the same method is shown; other human cytokines illustrated were not detected in panels of 9 to 10 normal donors using this method. Note that vertical scales differ.

Figure 2

Relationship of KSHV VL and key cytokines during KSHV-MCD flares. (A-C) KSHV VL was associated with vIL-6, hIL-6, and IL-10 during KSHV-MCD flares. For vIL-6, P < .001 by Jonckheere-Terpstra test for trend; for hIL-6 R = 0.55 and P < .001, and for IL-10 R = 0.73 and P < .001. (D) In contrast, levels of hIL-6 were not associated with the 3 ordered categories (illustrated: undetectable; detectable below 5500 pg/mL; and detectable above 5500 pg/mL) of vIL-6 levels during KSHV-MCD flares (P = .27 by Jonckheere-Terpstra trend test). Correlations between KSHV VL and flare-associated cytokines not pictured were weaker: for IL-1β, R = 0.21; for IL-5 R = −0.40, and for TNF-α R = −0.02. For hIL-6, the midpoint of levels found in 9 to 10 normal donors using the same method is shown.

Figure 3

Distinct human and vIL-6 cytokine profiles during KSHV-MCD activity. Three representative patients illustrate the 3 h/vIL-6 flare patterns encountered (h+VIL-6, hIL-6 alone, and vIL-6 alone). Levels of vIL-6, hIL-6, and KSHV VL in are shown during their initial therapy. Periods where KSHV-MCD clinical manifestations were present are shaded gray. In all cases, KSHV VL is elevated during flares. Three distinct cytokine profiles are seen: vIL-6 and hIL-6 elevation (left); vIL-6 elevation without hIL-6 (center), and hIL-6 with undetectable vIL-6 (right).