IL-1B Polymorphism in Association With Initial Intravenous Immunoglobulin Treatment Failure in Taiwanese Children With Kawasaki Disease

Weng, Ken‐Pen; Hsieh, Kai‐Sheng; Ho, Tsyr-Yuh; Huang, Shih-Hui; Lai, Chung-Ren; Chiu, Yi-Ten; Huang, Shih-Chang; Lin, Chu-Chuan; Hwang, Yu-Tung; Ger, Luo‐Ping

doi:10.1253/circj.cj-09-0664

Cited by 60 publications

(41 citation statements)

References 35 publications

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“…More recently, Fury et al demonstrated increased transcript abundance for IL-1 pathway genes in IVIG-resistant patients with KD [29]. Weng et al showed that IL-1β polymorphism was associated with initial IVIG treatment failure in Taiwanese children with KD [30]. Thus, higher IL-1β secretion and/or an IL-1β-mediated signaling pathway may be involved in the IVIG resistance in KD patients, and additional therapy by IL-1β blockade may help control the inflammation in the current IVIG-resistant patients with KD.…”

Section: Discussionmentioning

confidence: 99%

Anti‐inflammatory effects of high‐dose IgG on TNF‐α‐activated human coronary artery endothelial cells

et al. 2012

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High-dose infusion of IgG (IVIG) is used to treat autoimmune and inflammatory diseases, including Kawasaki disease (KD). Although the immunomodulatory effects of IVIG on blood cells such as macrophages have been well studied, its effects on tissue cells remain unclear. Here, we show that high-dose IgG specifically and completely inhibited TNF-α-induced, but not IL-1β-induced, secretion of proinflammatory cytokines such as G-CSF and IL-6 by cultured human coronary artery endothelial cells (HCAECs). Highdose IgG did not inhibit TNF-α-mediated early signaling events of the NF-κB and MAPK pathways but it potently inhibited gene expression of G-CSF and IL-6 12 h after TNF-α-stimulation. Interestingly, suppression of the G-CSF and IL-6 gene expression correlated closely with functional inhibition of a transcription factor, C/EBPδ, whose binding sites in the promoters of G-CSF and IL-6 have been shown to be critical for their transcriptional activation. Furthermore, the inhibitory effect of intact IgG on HCAECs was exerted mainly via its F(ab') 2 fragment, and not its Fc fragment. These findings suggest that the clinical effects of IVIG on KD patients are at least in part due to its direct anti-inflammatory effects on the coronary endothelium, which is a major lesion site in the pathogenesis of KD. Keywords:Coronary artery endothelial cells r IVIG r Kawasaki disease r TNF-α Supporting Information available online IntroductionIntravenous infusion of IgG was originally used as a replacement therapy for patients with hypogammaglobulinemia in the Correspondence: Dr. Akio Matsuda e-mail: amatsuda@nch.go.jp early 1950s. High-dose infusion of IgG (IVIG) is now used to treat autoimmune and inflammatory diseases such as idiopathic thrombocytopenic purpura, Guillain-Barre syndrome, and Kawasaki disease (KD). To date, a number of possible mechanisms for the immunomodulatory and anti-inflammatory effects of IVIG therapy have been described [1,2] KD is an acute systemic vasculitis seen in infants and young children [9,10], and it is frequently associated with coronary artery aneurysms [11]. IVIG is a well-established standard therapy for KD that effectively reduces systemic inflammation and the incidence of coronary artery lesions (CALs) [12][13][14]. The clinical evidence strongly suggests that IVIG exerts its beneficial effects by attenuating coronary artery inflammation. However, the mechanisms underlying these clinical effects of IVIG on coronary endothelium are not well understood, and some patients do not respond to IVIG and develop CALs. Thus, we examined the in vitro effects of high-dose IgG on cultured human coronary artery endothelial cells (HCAECs), which is a major lesion site in the pathogenesis of KD.We used TNF-α as an inflammatory stimulus in most of our in vitro experiments for the following reasons. First, during the acute phase of KD, serum levels of TNF-α are significantly elevated and correlate with the incidence of CALs in acute KD patients [15,16]. Second, TNF-α was shown to be necessary for induction of coro...

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Section: Discussionmentioning

confidence: 99%

Anti‐inflammatory effects of high‐dose IgG on TNF‐α‐activated human coronary artery endothelial cells

et al. 2012

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“…32,33 Treatment with infliximab might also be an initial therapy for high-risk KD patients. 25 Our previous study showed an effect of IL-1B polymorphism on the association with IVIG resistance in Taiwanese children with KD, 34 which suggests the potential usefulness of monoclonal antibodies to IL-1, such as anakinra, for IVIG-resistant patients. 35 Other immunosuppressive therapies, including cyclophosphamide, 36 methotrexate, 37 and plasma exchange, 38 have been used in the treatment of refractory KD.…”

Section: Other Treatmentsmentioning

confidence: 98%

Recent advances in the treatment of Kawasaki disease

Weng

Lin

et al. 2011

Journal of the Chinese Medical Association

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Kawasaki disease (KD) is acute systemic vasculitis that occurs mainly in infants and children under 5 years of age. The etiology of KD remains unknown. KD is liable to be complicated by coronary artery lesions (CALs), which develop in approximately 15-25% of untreated KD children and in approximately 5% of KD children after intravenous immunoglobulin (IVIG) therapy. A single high dose of IVIG (2 g/kg) is the gold standard therapy in the acute stage of KD. However, approximately 8--38% of children are unresponsive to initial IVIG treatment and at increased risk for CAL development. Anti-inflammatory high doses of aspirin are recommended in conjunction with IVIG, but our study demonstrated that there is no evidence of efficacy in preventing CAL development. The usefulness of steroids in initial therapy for KD or treatment of IVIG-resistant patients is not well established. Other immunosuppressive therapies, including infliximab, have been used in the treatment of refractory KD, but merit additional investigation. Subclinical atherosclerosis may develop early in KD patients, which makes early initiation of therapy to improve chronic inflammation an important issue. Future multicenter studies may help to define the optimal management of KD patients.

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“…IL-1β plays a critical role in broad spectrum of diseases, including chronic inflammatory diseases such as rheumatoid arthritis, metabolic syndrome, diabetes, atherosclerosis and more recently was linked to Kawasaki Disease vasculitis 25, 36–41 . IL-1α also plays a critical role in chronic inflammation and studies suggest that IL-1α can regulate IL-1β secretion 37, 42–44 .…”

Section: Introductionmentioning

confidence: 99%

Role of Interleukin-1 Signaling in a Mouse Model of Kawasaki Disease–Associated Abdominal Aortic Aneurysm

Wakita

Kurashima

Crother

et al. 2016

ATVB

127

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Objective Kawasaki disease (KD) is the most common cause of acquired cardiac disease in US children. In addition to coronary artery abnormalities and aneurysms, it can be associated with systemic arterial aneurysms. We evaluated the development of systemic arterial dilatation and aneurysms, including abdominal aortic aneurysm (AAA) in the Lactobacillus casei cell wall extract (LCWE)-induced KD vasculitis mouse model. Methods and Results We discovered that in addition to aortitis, coronary arteritis and myocarditis, the LCWE-induced KD mouse model is also associated with abdominal aorta dilatation and AAA, as well as renal and iliac artery aneurysms. AAA induced in KD mice was exclusively infrarenal, both fusiform and saccular, with intimal proliferation, myofibroblastic proliferation, break in the elastin layer, vascular smooth muscle cell loss, and inflammatory cell accumulation in the media and adventitia. Il1r−/−, Il1a−/−, and Il1a−/− mice were protected from KD associated AAA. Infiltrating CD11c+ macrophages produced active caspase-1 and caspase-1 or NLRP3 deficiency inhibited AAA formation. Treatment with IL-1R antagonist (Anakinra), anti-IL-1α, or anti-IL-1β mAb blocked LCWE-induced AAA formation. Conclusions Similar to clinical KD, the LCWE-induced KD vasculitis mouse model can also be accompanied by AAA formation. Both IL-1α and IL-1β play a key role, and that use of an IL-1R blocking agent that inhibits both pathways may be a promising therapeutic target not only for KD coronary arteritis, but also for the other systemic arterial aneurysms including AAA that maybe seen in severe cases of KD. The LCWE-induced vasculitis model may also represent an alternative model for AAA disease.

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IL-1B Polymorphism in Association With Initial Intravenous Immunoglobulin Treatment Failure in Taiwanese Children With Kawasaki Disease

Cited by 60 publications

References 35 publications

Anti‐inflammatory effects of high‐dose IgG on TNF‐α‐activated human coronary artery endothelial cells

Anti‐inflammatory effects of high‐dose IgG on TNF‐α‐activated human coronary artery endothelial cells

Recent advances in the treatment of Kawasaki disease

Role of Interleukin-1 Signaling in a Mouse Model of Kawasaki Disease–Associated Abdominal Aortic Aneurysm

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