Abstract
Innate immune activity plays an essential role in the development of Kawasaki disease (KD) vasculitis. Extracellular release of high mobility group box-1 (HMGB-1), an endogenous damage-associated molecular pattern protein that can activate the innate immune system and drive host inflammatory responses, may contribute to the development of coronary artery abnormalities in KD. Prednisolone (PSL) added to intravenous immunoglobulin treatment for acute KD may reduce such abnormalities. Here, we evaluate the dynamics of HMGB-1 and therapeutic effects of PSL on HMGB-1-mediated inflammatory pathways on KD vasculitis in vitro. Serum samples were collected prior to initial treatment from patients with KD, systemic juvenile idiopathic arthritis (sJIA), and from healthy controls (VH), then incubated with human coronary artery endothelial cells (HCAECs). Following treatment of KD serum-activated HCAECs with PSL or PBS as a control, effects on the HMGB-1 signaling pathway were evaluated. Compared to that from VH and sJIA, KD serum activation induced HCAEC cytotoxicity and triggered extracellular release of HMGB-1. KD serum-activated HCAECs up-regulated extracellular signal-regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK) and, p38 phosphorylation in the cytoplasm and nuclear factor kappa B (NF-κB) phosphorylation in the nucleus and increased interleukin (IL)-1β and tumor necrosis factor (TNF)-α production. PSL treatment of KD serum-activated HCAECs inhibited extracellular release of HMGB-1, down-regulated ERK1/2, JNK, p38, and NF-κB signaling pathways, and decreased IL-1β and TNF-α production. Our findings suggest that extracellular HMGB-1 plays an important role in mediating KD pathogenesis and that PSL treatment during the acute phase of KD may ameliorate HMGB-1-mediated inflammatory responses in KD vasculitis.
Highlights
Kawasaki disease (KD), an acute systemic vasculitis of unknown etiology, commonly occurs in children [1], and can lead to complex coronary artery abnormalities (CAAs)
We demonstrated that serum obtained from patients with KD prior to intravenous immunoglobulin (IVIG) treatment exhibited a cytotoxic effect on human coronary artery endothelial cells (HCAECs) compared to that from healthy controls and patients with systemic juvenile idiopathic arthritis (sJIA), in addition to triggering extracellular release of High mobility group box-1 (HMGB-1), up-regulating nuclear factor kappaB (NF-kB)-mediated inflammatory responses, and increasing IL-1b and tumor necrosis factor (TNF)-a production
Our results are in line with this pathological process in which the KD serum induced stronger cytotoxicity to coronary endothelial cells than sJIA serum, there was no Prednisolone Suppresses HMGB-1 Inflammatory Responses B C
Summary
Kawasaki disease (KD), an acute systemic vasculitis of unknown etiology, commonly occurs in children [1], and can lead to complex coronary artery abnormalities (CAAs). Extracellular HMGB-1 coordinates cellular responses associated with immune system activation, cell migration, cell growth, and tissue repair and regeneration, and binds to receptors, such as receptor for advanced glycation end products (RAGE) and Toll-like receptors (TLRs) to activate proinflammatory responses. Nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 (NLRP3)-dependent endothelial cell pyroptosis via HMGB-1/ RAGE/cathepsin B signaling may contribute to coronary artery endothelial cell (CAEC) damage in KD vasculitis [18]. DAMP-mediated innate immune system activation may facilitate pathological inflammatory responses in KD vasculitis
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