Hypercytokinemia is Not Originated from Peripheral Mononuclear Cells at Acute Phase of Kawasaki Disease

Abstract

Immune activation and generalized vasculitis are two central features of Kawasaki disease (KD). Recent observations indicated that serum levels of cytokines including interferon(INF)- γ, tumor necrosis factor (TNF)- α and interleukin (IL)-1 are remarkably increased, and that the administration of intravenous γ-globulin (IVGG) reduces the levels of elevated cytokines. Objective: We examined whether the plasma exchange (PE) for intractable KD cases reduces the elevated serum cytokines, and whether hypercytokinemia is originated from peripheral mononuclear cells at acute phase. Materials and Methods: We first compared the serum levels of cytokines between pre- and post-treatment of IVGG (8 cases) and PE (8 cases), using ELISA and cytometric bead array (CBA) system (Becton & Dickinson). For 4 cases among them, we investigated the messenger RNA levels of several cytokines in peripheral mononuclear cells at acute phase, using ribonuclease protection assay (RPA) system (Becton & Dickinson). Results: In sera of the children intractable to IVGG, increased levels of cytokines were detected such as INF-γ, IL-6, IL-10 and soluble TNF receptor (sTNFR). After PE therapy, serum levels of them markedly decreased to the normal ranges (INF-γ: 9.1 ± 13.4 →4.0 ± 6.4 pg/ml, IL-6: 67.5 ± 74.3→6.6 ± 8.4 pg/ml, IL-10: 14.1 ± 5.1→7.4 ± 2.1 pg/ml, sTNFR: 2521.9 ± 728.2→1338.2 ± 575.9 pg/ml). However, RPA analysis demonstrated that messenger RNA levels of several cytokines at acute phase were undetectable in both pre- and post-treatment of PE in peripheral mononuclear cells. Discussion: These findings suggested that the effectiveness of IVGG and PE treatment for KD will be attributed to the reduction of proinflammatory cytokine levels in serum, and that the increased levels of proinflammatory cytokines were originated not from the circulating mononuclear cells, but presumably from in situ lymphocytes and macrophages located at inflammatory lesion such as vasculitis lesion.