interleukin-8 and Mucocutaneous-Lymph-Node-Syndrome

Kawasaki disease (KD) is a systemic vasculitis preferentially affecting coronary arteries. Extensive monocytes/macrophages infiltrate in the vascular lesions, implying the involvement of a chemotactic cytokine in their recruitment. We investigated the role of monocyte chemoattractant protein-1 (MCP-1, also termed monocyte chemotactic and activating factor) in KD. In the immunohistochemical studies using the cardiac tissues of patients with fatal KD, MCP-1 but not interleukin (IL) -8 or macrophage inflammatory protein-1alpha was localized at the extracellular matrix associated with mononuclear cellular infiltration. The sites of MCP-1 expression correlated with the distribution of the acute inflammation, including early coronary vasculitis. In prospectively studied patients with KD, circulating levels of MCP-1, IL-8, tumor necrosis factor alpha (TNF-alpha), and IL-1alpha were elevated in 73, 77, 57, and 0% of samples before gamma globulin (GG) treatment (400 mg/kg x 5 days = total 2 g/kg), respectively, compared with respective control values. GG treatment correlated with a rapid decrease in the circulating levels of MCP-1 (P = 0.001) but not IL-8 (P = 0.19) or TNF-alpha (P = 0.33). In the sensitive Western blotting, MCP-1 bound to GG. Furthermore, GG inhibited the MCP-1-induced Ca2+ influx in a human monocytic cell line in vitro. These findings suggest a role of MCP-1 in KD, and indicate that GG treatment may block MCP-1 activity, thus alleviating KD vasculitis.

Topics: Blotting, Western; Calcium; Cell Line; Chemokine CCL2; Chemokine CCL4; Child; Child, Preschool; gamma-Globulins; Humans; Immunohistochemistry; Infant; Interleukin-1; Interleukin-8; Macrophage Inflammatory Proteins; Monocytes; Mucocutaneous Lymph Node Syndrome; Myocardium; Tumor Necrosis Factor-alpha

Kawasaki disease (KD) is an acute, self-limiting, febrile systemic vasculitis of unknown cause associated with the development of coronary artery lesions (CALs) during childhood. Damage-associated molecular patterns (DAMPs) from cell death and oxidative stress have been shown to be involved in the development of KD vasculitis. Interleukin (IL)-33 is released from damaged endothelial cells and acts as a DAMP. We studied whether IL-33 and its receptor (ST2) might be involved in KD pathogenesis. Serum levels of soluble ST2 (sST2) in KD patients were measured before their first therapy. Furthermore, we investigated the impact of IL-33 on human coronary artery endothelial cells (HCAECs). Serum levels of sST2 were significantly higher in KD patients with CALs than in those with normal coronary arteries. In vitro, IL-33 upregulated the expression of ST2L and increased production of sST2, IL-6, IL-8, and monocyte chemoattractant protein-1 in HCAECs in a time- and concentration-dependent manner. Moreover, IL-33 induced significantly greater production of IL-6 and IL-8 in HCAECs compared to the condition stimulated with isoconcentration of tumor necrosis factor-α. The results of the present study suggest that the IL-33/ST2 axis might be involved in the development of KD vasculitis. The IL-33/ST2 axis may be a therapeutic target for the treatment of KD.

Topics: Biomarkers; Endothelial Cells; Humans; Interleukin-1 Receptor-Like 1 Protein; Interleukin-33; Interleukin-6; Interleukin-8; Mucocutaneous Lymph Node Syndrome

SARS-CoV-2 infection in children can trigger cardiovascular manifestations potentially requiring an intensive treatment and defining a new entity named Multisystem Inflammatory Syndrome in Children (MIS-C), whose features partially overlap with Kawasaki Disease (KD). A cross-sectional study including all diagnoses of MIS-C and KD from April 2020 to May 2021 in our metropolitan area was conducted evaluating clinical, laboratory (including immunological response, cytokines, and markers of myocardial damage), and cardiac (coronary and non-coronary) features at onset of the diseases. Evolution of ventricular dysfunction, valve regurgitations, and coronary lesions was documented. The severity of the disease was also considered based on the need for inotropic support and ICU admission. Twenty-four MIS-C were diagnosed (14 boys, median age 82 months): 13/24 cases (54.17%) presented left ventricular dysfunction, 12/24 (50%) required inotropic support, and 10/24 (41.67%) developed coronary anomalies (CALs). All patients received steroids and IVIG at a median time of 5 days (IQR1:4, IQR3:6.5) from onset of fever and heart function normalized 6 days (IQR1: 5, IQR3: 7) after therapy, while CALs persisted in one. One patient (12.5%) required infliximab because of refractory disease and still presented CALs 18 days after therapy. During the same study period, 15 KD were diagnosed: none had ventricular dysfunction, while 7/15 (46.67%) developed CALs. Three out of 15 patients (20%) still presented CALs 46 days from onset. Compared to KD, MIS-C pts have significantly higher IL8 and similar lymphocytes subpopulations. Despite a more severe presentation and initial cardiac findings compared to KD, the myocardial injury in MIS-C has a rapid response to immunomodulatory treatment (median time 6 days), in terms of ventricular function, valve regurgitations, and troponin. Incidence of CALs is similar at onset, but it tends to regress in most of the cases of MIS-C differently than in KD where CALs persist in up to 40% in the subacute stage after treatment.

Topics: Adolescent; Child; Child, Preschool; COVID-19; Cross-Sectional Studies; Female; Humans; Infant; Infant, Newborn; Interleukin-10; Interleukin-8; Italy; Male; Mucocutaneous Lymph Node Syndrome; Myocardium; Prospective Studies; SARS-CoV-2; Systemic Inflammatory Response Syndrome; Ventricular Dysfunction, Left

Inflammation of endothelial cells (ECs) plays an important role in the pathogenesis of coronary artery lesions (CALs) in Kawasaki disease (KD). Semaphorin 4D (Sema4D) is the first semaphorin shown to have immunoregulatory functions by interacting with its receptors-plexin Bs. Recently, Sema4D has been reported to exert a proinflammatory effect on the endothelium and to be involved in cardiovascular disease. However, the role of Sema4D in KD remains unknown. This study was aimed at revealing the change of soluble Sema4D (sSema4D) in the serum of patients with KD and the effect of the sSema4D-plexin axis on the production of proinflammatory cytokines from human coronary endothelial cells (HCAECs) stimulated with sera from KD patients. Our results showed that serum sSema4D levels were specifically elevated in KD patients, especially in those with CALs, and correlated positively with disease severity and serum concentrations of interleukin- (IL-) 1

Topics: ADAM17 Protein; Antigens, CD; Case-Control Studies; Child, Preschool; Coronary Vessels; Cytokines; Endothelial Cells; Female; Humans; Infant; Inflammation; Interleukin-1; Interleukin-6; Interleukin-8; Male; Mucocutaneous Lymph Node Syndrome; Nerve Tissue Proteins; Neutrophils; Receptors, Cell Surface; Semaphorins

To study the role of triggering receptor expressed on myeloid cells-1(TREM-1) in the pathogenesis of Kawasaki disease (KD).. Based on color Doppler examination results, 45 children with KD were classified into two groups: coronary artery lesions (CAL group) and no coronary artery lesions (NCAL group). Fifteen children with fever caused by respiratory infection (fever control group) and fifteen healthy children (normal control group) served as controls. Real-time fluorescence quantitative PCR was used to detect the expression of TREM-1 mRNA and DNAX-activating protein 12 (DAP12) mRNA in peripheral blood mononuclear cells (PBMC). ELISA was used to detect the expression of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), DAP12, monocyte chemoattractant protein-1(MCP-1), interleukin-8 (IL-8) proteins levels.. The mean serum protein concentrations of sTREM-1 and DAP12 and the expression levels of TREM-1 mRNA and DAP12 mRNA in PBMC in 45 children with KD (KD group) were significantly higher than in the two control groups (P<0.05). The levels of sTREM-1 protein and TREM-1 mRNA in the CAL subgroup were significantly higher than in the NCAL subgroup (P<0.05). The serum protein concentrations of MCP-1 and IL-8 in the KD group were significantly higher than in the two control groups (P<0.05). The MCP-1 protein level in the CAL subgroup was significantly higher than in the NCAL subgroup (P<0.05). In children with KD, there was a positive correlation between serum sTREM-1 and MCP-1 levels (r=0.523, P<0.05).. TREM-1 activation may be involved in the development of KD.

Topics: Chemokine CCL2; Child; Child, Preschool; Female; Humans; Infant; Interleukin-8; Male; Membrane Glycoproteins; Mucocutaneous Lymph Node Syndrome; Receptors, Immunologic; RNA, Messenger; Triggering Receptor Expressed on Myeloid Cells-1

Kawasaki disease is an acute febrile vasculitis of childhood that is associated with elevated production of inflammatory cytokines, causing damage to the coronary arteries. The production of proinflammatory cytokines and expression of adhesion molecules in human coronary arterial endothelial cells (HCAECs) is regulated by nuclear transcription factor-κB (NF-κB) activation. We have previously reported that the active form of vitamin D, 1α,25-dihydroxyvitamin D(3) (1α,25-(OH)(2)D(3)), inhibits tumor necrosis factor-α (TNF-α)-induced NF-κB activation. In this study, we examined the anti-inflammatory effects of 1α,25-(OH)(2)D(3) on TNF-α-induced adhesion molecule expression (vascular cellular adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1)) and cytokine production (interleukin-6 (IL-6) and IL-8) in HCAECs. Pretreatment with 1α,25-(OH)(2)D(3) significantly inhibited TNF-α-induced VCAM-1 expression and IL-8 production in HCAECs. Our results suggest that adjunctive 1α,25-(OH)(2)D(3) therapy may modulate the inflammatory response during Kawasaki disease vasculitis.

Topics: Cell Adhesion; Coronary Vessels; Endothelial Cells; Endothelium, Vascular; Gene Expression Regulation; Humans; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; Mucocutaneous Lymph Node Syndrome; RNA, Messenger; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1; Vitamin D

Topics: Acetylglucosaminidase; C-Reactive Protein; Case-Control Studies; Chemokine CCL2; Child, Preschool; Humans; Interleukin-8; Mucocutaneous Lymph Node Syndrome

The aim of the present study was to investigate whether neutrophils are early effector cells for vascular endothelial damage in the acute phase of Kawasaki disease (KD) by examining serial changes in neutrophil counts and serum levels of neutrophil activation cytokines, such as granulocyte colony stimulating factor (G-CSF) and interleukin (IL)-8.. From October 1994 to June 1998, a total of 52 patients with KD were included in the study. Thirty-three patients had some infectious diseases, while 20 healthy children served as control subjects. Serial changes in neutrophils were counted by the optimal Wright-Giemsa staining method and serum levels of IL-8 and G-CSF in patients with KD were measured by an enzyme-linked immunosorbent assay system.. Serum G-CSF levels both before and after intravenous immunoglobulin therapy (IVIG; P<0.05) and neutrophil counts after IVIG (P<0.005) were higher in KD patients with coronary arterial lesions (CAL) than those without CAL. However, serum IL-8 levels before and after IVIG showed no significant differences in these two groups.. These data suggest that neutrophils may be important as early effector cells for vascular endothelial damage and that G-CSF may play a more important role than IL-8 in KD.

Topics: Child; Child, Preschool; Granulocyte Colony-Stimulating Factor; Humans; Immunoglobulins, Intravenous; Infant; Interleukin-8; Leukocyte Count; Mucocutaneous Lymph Node Syndrome; Neutrophil Activation

Intravenous immune gamma-globulin (IVIG) is used successfully in the treatment of Kawasaki disease, with dose-dependent rapid resolution of symptoms such as fever and irritability and a decrease in ESR, WBCs, and platelets. The mode of action of IVIG in reducing this inflammatory response is not clearly understood. Recently anticytokine antibodies in IVIG have been demonstrated. Serum levels of proinflammatory cytokines have been shown to be elevated in patients with Kawasaki disease. The cytokine interleukin-6 (IL-6) is involved in the de novo production of acute-phase proteins by hepatocytes and cause thrombocytosis and fever in response to tissue injury. Patients receiving parenteral recombinant human IL-6 have dose-dependently experienced fever, malaise, chills, and acute-phase reaction. With high IL-6 concentrations, central nervous system toxicity has also been reported and IL-6 has been thought to mediate endothelial damage. We evaluated the response of stimulated blood cells of 12 normal children to IVIG in the release of the cytokines IL-6, IL-8, TNF-alpha. and IL-6 receptor (sIL-6R). The levels of cytokines IL-6, IL-8, and TNF-alpha (but not sIL-6R) in peripheral blood induced by stimulation with LPS were markedly reduced (P < 0.008) within 3 hr when incubated with IVIG compared to without IVIG. Thus we demonstrated that cells of normal children respond to IVIG in vitro by reducing cytokines such as IL-8, TNF-alpha, and IL-6 without affecting the level of receptor sIL-6R during an acute inflammatory response. We also found significantly higher IL-6 levels in children with Kawasaki disease compared to children with blood culture-negative febrile illnesses. In five children with Kawasaki disease we measured serum IL-6 before and after IVIG and assessed the clinical response to IVIG therapy. Therapy with IVIG was followed by a rapid resolution of symptoms in Kawasaki disease, with a significant decrease in serum IL-6. The attenuation of proinflammatory cytokine responses, especially IL-6, following infusions of IVIG may play an integral role in the rapid resolution of symptoms and decrease in the acute-phase proteins in children with Kawasaki disease. Cells of normal children were found to respond to the IVIG in a manner similar to that of the Kawasaki children.

Topics: Blood Cells; Case-Control Studies; Child, Preschool; Cytokines; Humans; Immunoglobulins, Intravenous; In Vitro Techniques; Infant; Interleukin-6; Interleukin-8; Lipopolysaccharides; Mucocutaneous Lymph Node Syndrome; Receptors, Interleukin-6; Tumor Necrosis Factor-alpha

We investigated, by Northern blotting, ELISA, and a chemotaxis assay, the expression of IL-8 mRNA, the production of IL-8 protein, and the biological activity of mononuclear cells (MNC), polymorphonuclear neutrophils (PMN) and plasma, respectively, from patients with Kawasaki disease (KD) who received intravenous immunoglobulin (IVIG). IL-8 mRNA expression by MNC and PMN, the level of IL-8 protein, and the neutrophil chemoattractant activity within plasma were all increased in the acute phase of KD, and were significantly elevated following IVIG therapy. The level of chemotactic activity of neutrophils, but not that of monocytes, in response to F-met-leu-phe was decreased in patients with KD after IVIG. The increased expression of IL-8 in PMN and MNC, the increased plasma level of IL-8 and the decreased level of neutrophil chemotactic activity of the patients who received IVIG therapy might inhibit the accumulation of neutrophils at the sites of inflammation, and may thus reduce the risk of aneurysm formation.

Topics: Chemotactic Factors; Child, Preschool; gamma-Globulins; Gene Expression; Humans; Immunoglobulins, Intravenous; Infant; Interleukin-8; Leukocytes, Mononuclear; Mucocutaneous Lymph Node Syndrome; Neutrophils; RNA, Messenger

In this study, we measured serially the serum levels of cytokines including interleukin-6 (IL-6), IL-8, soluble IL-2 receptor (sIL-2R) and tumour necrosis factor alpha (TNF-alpha) in 60 patients with Kawasaki disease (KD) and evaluated the clinical significance of these cytokines in predicting coronary aneurysm formation. Of the 60 patients, 12 were complicated with coronary aneurysm. Blood samples were collected within the 1st week after onset of fever, then once a week for the 1st month, and once a month for another 5 months. The serum levels of IL-6, IL-8, sIL-2R and TNF alpha were measured using an ELISA or RIA method. Our results show that the changes in serum IL-6 and IL-8 were faster than those of sIL-2R and TNF alpha. Within the 1st week, the serum levels of IL-6 and IL-8 were significantly higher in the patients with than in those without coronary aneurysm (P < 0.001). In addition, the serum levels of IL-6 and IL-8 obtained in the 1st week were highly correlated (P < 0.001) with those of C-reactive protein and erythrocyte sedimentation rate, and the serum levels of sIL-2R and TNF alpha were also increased at the 1st week reaching the highest level in the 2nd week. In the 2nd week, the serum levels of sIL-2R and TNF alpha were significantly higher in the patients with than in those without coronary aneurysm (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Child, Preschool; Coronary Aneurysm; Female; Humans; Infant; Interleukin-6; Interleukin-8; Interleukins; Male; Mucocutaneous Lymph Node Syndrome; Receptors, Interleukin-2; Time Factors; Tumor Necrosis Factor-alpha

To determine the role of cytokines in Kawasaki disease, serial measurements of serum cytokine levels were done in 60 patients treated solely with aspirin. Coronary artery aneurysms later developed in 12 of them. The results suggest that elevated serum interleukin-6 and interleukin-8 levels during the first week of illness may be associated with a higher risk of coronary aneurysm formation.

Topics: Aspirin; Child, Preschool; Coronary Aneurysm; Female; Humans; Infant; Interleukin-6; Interleukin-8; Male; Mucocutaneous Lymph Node Syndrome; Prognosis; Tumor Necrosis Factor-alpha