J Immunol. 2025 Sep 16:vkaf245. doi: 10.1093/jimmun/vkaf245. Online ahead of print.
ABSTRACT
Kawasaki disease (KD) is the most common childhood vasculitis. Approximately 25% of KD patients are refractory to standard intravenous immunoglobulin (IVIG) therapy and frequently develop coronary artery lesions (CAL) that result in long-term complications. Transcriptome studies utilizing blood cells from KD patients and reported animal model studies had identified interleukin (IL)-1β as a crucial component of an essential immune pathway in the formation of CAL. We previously reported that high-dose immunoglobulin G (IgG) treatment completely inhibited tumor necrosis factor (TNF)-α-stimulated inflammatory responses in an in vitro human coronary artery endothelial cells (HCAECs) model. Here, we show that IL-1β, but not TNF-α, stimulation markedly induced nuclear protein expression of NF-kappa-B inhibitor zeta (IκBζ) in HCAECs. It is of particular significance that IL-1β-induced IκBζ expression is entirely refractory to high-dose IgG treatment. Therefore, IκBζ may be a critical factor in the IVIG-resistant vascular inflammatory responses in severe KD. Itaconate is a Krebs cycle-derived metabolite with several immunomodulatory effects. Dimethyl itaconate (DI), a membrane-permeable derivative of itaconate, can significantly suppress IL-1β-induced IκBζ expression in HCAECs. DI is an analog of dimethyl fumarate (DMF), which is already in clinical use for some diseases. Like DI, DMF suppressed IL-1β-induced IκBζ expression and subsequent production of inflammatory cytokines, including IL-6 and G-CSF. This study identified IκBζ as an essential inflammatory factor in IVIG-resistant inflammatory responses in HCAECs. Immunomodulatory substances, such as DI and/or DMF, may be therapeutically exploited as a novel drug to alleviate inflammation in severe IVIG-resistant KD patients.
PMID:40973123 | DOI:10.1093/jimmun/vkaf245