Abstract Objective To study the expression of serum cytokines, interleukin-38 (IL-38) and interleukin-1β (IL-1β) in the acute phase of Kawasaki disease (KD) in children and the association of IL-38 and IL-1β with inflammatory response in the acute phase and the development of coronary artery lesion (CAL).Methods A total of 40 children with KD who were hospitalized in the hospital between July 2015 and June 2016 were enrolled, with 21 children in the CAL group and 19 in the non-CAL (NCAL) group. Thirty healthy children and 19 children with infection and pyrexia, who were matched for sex and age, were enrolled as healthy control group and pyrexia control group respectively. ELISA was used to measure the serum levels of IL-38 and IL-1β in the 40 children in the acute phase of KD. Spearman's rank correlation analysis was used to investigate the correlations of IL-1β and IL-38 with interleukin-6 (IL-6), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), procalcitonin (PCT), N-terminal pro-brain natriuretic peptide (NTproBNP), triglyceride (TG), and total cholesterol (TC).Results The serum level of IL-38 in the children in the acute phase of KD was signifcantly lower than that in the healthy control group (P < 0.05), but signifcantly higher than that in the pyrexia control group (P < 0.05). There was no signifcant difference in the level of IL-38 between the CAL and NCAL groups (P > 0.05). The children in the acute phase of KD had a signifcantly higher level of IL-1β than the healthy control group (P < 0.05), while there was no significant difference between this group and the pyrexia control group (P > 0.05). There was also no signifcant difference in the level of IL-1β between the CAL and NCAL groups (P > 0.05). Serum IL-1β and IL-38 levels were not correlated with serum levels of CRP, ESR, PCT, IL-6, and NT-ProBNP or blood lipids (TG and TC) (P > 0.05).Conclusions IL-38 is involved in an inflammatory response in the acute phase of KD and may exert an anti-inflammatory effect, which is opposite to the effect of IL-1β to promote inflammatory response. However, there is no signifcant correlation between these two cytokines and the development of CAL in KD.
ZHANG Xin-Yan,HE Ting,LING Jia-Yun et al. Serum levels of interleukin-38 and interleukin-1β in the acute phase of Kawasaki disease in children[J]. CJCP, 2018, 20(7): 543-548.
ZHANG Xin-Yan,HE Ting,LING Jia-Yun et al. Serum levels of interleukin-38 and interleukin-1β in the acute phase of Kawasaki disease in children[J]. CJCP, 2018, 20(7): 543-548.
Shulman ST, Rowley AH. Kawasaki disease:insights into pathogenesis and approaches to treatment[J]. Nat Rev Rheumatol, 2015, 11(8):475-482.
[2]
Guo MM, Tseng WN, Ko CH, et al. Th17-and Treg-related cytokine and mRNA expression are associated with acute and resolving Kawasaki disease[J]. Allergy, 2015, 70(3):310-318.
[3]
Jia S, Li C, Wang G, et al. The T helper type 17/regulatory T cell imbalance in patients with acute Kawasaki disease[J]. Clin Exp Immunol, 2010, 162(1):131-137.
[4]
Barranco C. Vasculitis syndromes:Kawasaki disease is IL-1β-mediated[J]. Nat Rev Rheumatol, 2016, 12(12):693.
[5]
Alphonse MP, Duong TT, Shumitzu C, et al. Inositoltriphosphate 3-kinase C mediates inflammasome activation and treatment response in Kawasaki disease[J]. J Immunol, 2016, 197(9):3481-3489.
[6]
Garraud T, Harel M, Boutet MA, et al. The enigmatic role of IL-38 in inflammatory diseases[J]. Cytokine Growth Factor Rev, 2018, 39:26-35.
[7]
Boutet MA, Bart G, Penhoat M, et al. Distinct expression of interleukin (IL)-36α, β and γ, their antagonist IL-36Ra and IL-38 in psoriasis, rheumatoid arthritis and Crohn's disease[J]. Clin Exp Immunol, 2016, 184(2):159-173.
[8]
Hahn M, Frey S, Hueber AJ. The novel interleukin-1 cytokine family members in inflammatory diseases[J]. Curr Opin Rheumatol, 2017, 29(2):208-213.
[9]
Chu M, Chu IM, Yung EC, et al. Aberrant expression of novel cytokine IL-38 and regulatory T lymphocytes in childhood asthma[J]. Molecules, 2016, 21(7):e933.
[10]
Takeuchi Y, Seki T, Kobayashi N, et al. Analysis of serum IL-38 in juvenile-onset systemic lupus erythematosus[J]. Mod Rheumatol, 2018.[Epub ahead of print]
[11]
McCrindle BW, Rowley AH, Newburger JW, et al. Diagnosis, treatment, and long-term management of Kawasaki disease:a scientifc statement for health professionals from the American Heart Association[J]. Circulation, 2017, 135(17):e927-e999.
[12]
Burns JC, Koné-Paut I, Kuijpers T, et al. Review:found in translation:international initiatives pursuing interleukin-1 blockade for treatment of acute Kawasaki disease[J]. Arthritis Rheumatol, 2017, 69(2):268-276.
[13]
Cohen S, Tacke CE, Straver B, et al. A child with severe relapsing Kawasaki disease rescued by IL-1 receptor blockade and extracorporeal membrane oxygenation[J]. Ann Rheum Dis, 2012, 71(12):2059-2061.
[14]
Yuan X, Peng X, Li Y, et al. Role of IL-38 and its related cytokines in inflammation[J]. Mediators Inflamm, 2015, 2015:807976.
[15]
Lin H, Ho AS, Haley-Vicente D, et al. Cloning and characterization of IL-1HY2, a novel interleukin-1 family member[J]. J Biol Chem, 2001, 276(23):20597-20602.
[16]
van de Veerdonk FL, Stoeckman AK, Wu G, et al. IL-38 binds to the IL-36 receptor and has biological effects on immune cells similar to IL-36 receptor antagonist[J]. Proc Natl Acad Sci U S A, 2012, 109(8):3001-3005.
[17]
Leung DY, Geha RS, Newburger JW, et al. Two monokines, interleukin 1 and tumor necrosis factor, render cultured vascular endothelial cells susceptible to lysis by antibodies circulating during Kawasaki syndrome[J]. J Exp Med, 1986, 164(6):1958-1972.
[18]
Leung DY, Cotran RS, Kurt-Jones E, et al. Endothelial cell activation and high interleukin-1 secretion in the pathogenesis of acute Kawasaki disease[J]. Lancet, 1989, 2(8675):1298-1302.
[19]
Lee Y, Schulte DJ, Shimada K, et al. Interleukin-1β is crucial for the induction of coronary artery inflammation in a mouse model of Kawasaki disease[J]. Circulation, 2012, 125(12):1542-1550.
[20]
Lee Y, Wakita D, Dagvadorj J, et al. IL-1 signaling is critically required in stromal cells in Kawasaki disease vasculitis mouse model:role of both IL-1α and IL-1β[J]. Arterioscler Thromb Vasc Biol, 2015, 35(12):2605-2616.
[21]
Ogata S, Tremoulet AH, Sato Y, et al. Coronary artery outcomes among children with Kawasaki disease in the United States and Japan[J]. Int J Cardiol, 2013, 168(4):3825-3828.
[22]
Shafferman A, Birmingham JD, Cron RQ. High dose Anakinra for treatment of severe neonatal Kawasaki disease:a case report[J]. Pediatr Rheumatol Online J, 2014, 12:26.
[23]
Alphonse MP, Duong TT, Shumitzu C, et al. Inositoltriphosphate 3-kinase C mediates inflammasome activation and treatment response in Kawasaki disease[J]. J Immunol, 2016, 197(9):3481-3489.
[24]
van de Veerdonk FL, de Graaf DM, Joosten LA, et al. Biology of IL-38 and its role in disease[J]. Immunol Rev, 2018, 281(1):191-196.
[25]
Rudloff I, Godsell J, Nold-Petry CA, et al. Brief report:interleukin-38 exerts antiinflammatory functions and is associated with disease activity in systemic lupus erythematosus[J]. Arthritis Rheumatol, 2015, 67(12):3219-3225.
[26]
Zhong Y, Yu K, Wang X, et al. Elevated plasma IL-38 concentrations in patients with acute ST-segment elevation myocardial infarction and their dynamics after reperfusion treatment[J]. Mediators Inflamm, 2015, 2015:490120.
[27]
Boutet MA, Najm A, Bart G, et al. IL-38 overexpression induces anti-inflammatory effects in mice arthritis models and in human macrophages in vitro[J]. Ann Rheum Dis, 2017, 76(7):1304-1312.
Chu M, Tam LS, Zhu J, et al. In vivo anti-inflammatory activities of novel cytokine IL-38 in Murphy Roths Large (MRL)/lpr mice[J]. Immunobiology, 2017, 222(3):483-493.
[30]
Zhang J, Zhao R, Chen J, et al. The effect of interleukin 38 on angiogenesis in a model of oxygen-induced retinopathy[J]. Sci Rep, 2017, 7(1):2756.
[31]
Mora J, Schlemmer A, Wittig I, et al. Interleukin-38 is released from apoptotic cells to limit inflammatory macrophage responses[J]. J Mol Cell Biol, 2016.[Epub ahead of print].
