Abstract
BackgroundKawasaki disease (KD) is the most common pediatric systemic vasculitides of unknown etiology. Recent clinical studies led to reappraisal of the usefulness of initial combination therapy of intravenous immunoglobulin (IVIG) plus a corticosteroid for patients with severe KD. However, the molecular mechanisms underlying the clinical benefits of that combination therapy remain unclear. Here, we used cultured human coronary artery endothelial cells (HCAECs), as a mimic of KD, to study the possible mechanisms responsible for the clinical benefits of adding a corticosteroid to standard IVIG therapy for patients with severe KD.MethodsHCAECs were stimulated with TNF-α, IL-1α or IL-1β in the presence and absence of high-dose IgG and/or dexamethasone (DEX). The mRNA and protein concentrations for high-mobility group box-1 (HMGB1), IL-1α, IL-6 and granulocyte-colony stimulating factor (G-CSF) in the culture supernatants were measured by quantitative PCR (qPCR) and ELISA, respectively. Apoptosis was evaluated by the caspase 3/7 activities.ResultsDEX, but not IgG, significantly inhibited apoptosis caused by inflammatory stimuli, resulting in effective reduction of HMGB1 and IL-1α protein release by HCAECs. As previously reported, DEX or IgG alone significantly suppressed TNF-α-induced production of IL-6 and G-CSF and mRNA expression, but induction of those cytokines by IL-1 s (IL-1α and IL-1β) was resistant to high-dose IgG.ConclusionsA corticosteroid can effectively inhibit the release of HMGB1 and IL-1α, which may be involved in IVIG resistance in KD. Since high-dose IgG does not have such beneficial anti-cytotoxic effects, adding a corticosteroid to standard IVIG therapy may help prevent the progression of IVIG resistance in KD.
Highlights
Kawasaki disease (KD) is the most common pediatric systemic vasculitides of unknown etiology
It is of note that high-mobility group box-1 (HMGB1) protein release by the human coronary artery endothelial cells (HCAECs) was not suppressed at all by IgG treatment, whereas it was significantly suppressed by DEX treatment, for each of the tested cytokine stimuli (Fig. 1a)
Effects of high-dose IgG and DEX on expression of IL-6 and granulocyte-colony stimulating factor (G-CSF) in HCAECs stimulated with inflammatory cytokines We examined the effects of high-dose IgG and DEX on cytokine-induced expression of IL-6 and Granulocyte-colony stimulating factor (GCSF), which are crucially involved in the pathogenesis of KD [16, 17]
Summary
Kawasaki disease (KD) is the most common pediatric systemic vasculitides of unknown etiology. Recent clinical studies led to reappraisal of the usefulness of initial combination therapy of intravenous immunoglobulin (IVIG) plus a corticosteroid for patients with severe KD. We used cultured human coronary artery endothelial cells (HCAECs), as a mimic of KD, to study the possible mechanisms responsible for the clinical benefits of adding a corticosteroid to standard IVIG therapy for patients with severe KD. Kawasaki disease (KD), first described by Dr Tomisaku Kawasaki in 1967 in Japan [1], is one of the most common pediatric systemic vasculitides of unknown etiology. As treatment options for IVIG-resistant KD patients, there have been reports of the usefulness of additional IVIG, corticosteroids, ulinastatin [5], plasma exchange [6] and anti-TNF-α therapy [7]
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