Background: 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. However, the molecular mechanisms underlying the clinical benefits of early introduction of a corticosteroid to IVIG for severe KD patients remain unclear. We used cultured human coronary artery endothelial cells (HCAECs), which mimic the main lesion sites of KD, in an attempt to elucidate the mechanisms underlying the clinical benefits accruing from adding a corticosteroid to standard IVIG therapy for patients with KD.
Methods: HCAECs were stimulated with TNF-α, IL-1α or IL-1β in the presence and absence of IVIG 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.
Results: DEX, but not IVIG, 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 IVIG alone significantly suppressed TNF-α-induced production of IL-6 and G-CSF and mRNA expression, but induction of those cytokines by IL-1s (IL-1α and IL-1β) was resistant to IVIG.
Conclusions: A corticosteroid can effectively inhibit the release of HMGB1 and IL-1α, which may be involved in IVIG resistance in KD. Since IVIG 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.