title: Effects of IL-33/ST2 pathway in acute inflammation on tissue damage, antioxidative parameters, magnesium concentration and cytokines profile.
abstract: The aim of this study was to examine the role of IL-33/ST2 pathway in a pathogenesis of acute inflammation and its effects on tissue damage, antioxidative capacity, magnesium concentration and cytokine profile in acutely inflamed tissue.
  
  
  
  Male mice were randomly divided in four groups: wild-type control group (WT-C), ST2 knockout control group (KO-C), wild-type inflammatory group (WT-I), and ST2 knockout inflammatory group (KO-I). Acute inflammation was induced in WT-I and KO-I by intramuscular injection of turpentine oil, while mice in WT-C and KO-C were treated with saline. After 12h, animals were euthanized, and blood was collected for determination of creatine kinase (CK) and aspartate transaminase (AST) activity. The treated tissue was used for histopathological analysis, determination of volume density of inflammatory infiltrate (Vdii) and necrotic fiber (Vdnf), gene expression of interleukin (IL)-33, ST2, tumor necrosis factor alpha (TNF-alpha), IL-6, IL-12p35, and transforming growth factor beta (TGF-beta), concentration of magnesium (Mg), copper (Cu), selenium (Se), manganese (Mn) and reduced glutathione (GSH), and superoxide dismutase (SOD) and glutathione peroxidase (GPx) activity.
  
  
  
  Presence of inflammatory infiltration and necrosis in the treated tissue was histopathologically confirmed in WT-I and KO-I. Vdii was significantly higher in WT-I when compared to KO-I, whereas Vdnf did not significantly differ between WT-I and KO-I. CK and AST significantly increased in both inflammatory groups when compared to corresponding control groups. However, the values of CK and AST were significantly higher in WT-I than in KO-I. Mg in the treated tissue was significantly lower in WT-I in comparison to WT-C and KO-I, while there was no significant difference between KO-C and KO-I. There was no significant difference in Cu, Se, and Mn in the treated tissue between WT-C, KO-C, WT-I and KO-I. Gene expression of IL-33 in the treated tissue increased in both inflammatory groups when compared to the corresponding control groups, but it was significantly higher in KO-I than in WT-I. Gene expression of ST2 in the treated tissue was significantly higher in WT-I than in WT-C. Gene expression of TNF-alpha, IL-6, and IL-12p35 in the treated tissue was significantly higher in WT-I and KO-I than in the corresponding control groups, and IL-6 was significantly higher in KO-C than in WT-C. TGF-beta gene expression in the treated tissue was significantly higher in KO-I when compared to WT-I, while there was no difference between WT-C and KO-C. SOD activity decreased at the site of acute inflammation in both inflammatory groups, while the GPx activity increased. GSH in the treated tissue was significantly higher in KO-I than in KO-C or WT-I.
  
  
  
  The results of our study have indicated, to our knowledge for the first time, that IL-33/ST2 pathway plays a role in enhancing inflammation and tissue damage at the site of acute inflammation by affecting the concentration of magnesium and GSH, important for antioxidative capacity, as well as gene expression of anti-inflammatory cytokine TGF-beta.
authors.affiliation: Department of Pathophysiology, Faculty of Medicine, University of Belgrade, Dr Subotica 8, 11000 Belgrade, Serbia. Electronic address: marija.stankovic.med@gmail.com.
authors.forename: Marija S
authors.initials: MS
authors.lastname: Stankovic
authors.affiliation: Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr Subotica 8, 11000 Belgrade, Serbia.
authors.forename: Kristina
authors.initials: K
authors.lastname: Janjetovic
authors.affiliation: Institute of Clinical and Medical Biochemistry, School of Medicine, University of Belgrade, Pasterova 2, 11000 Belgrade, Serbia.
authors.forename: Milica
authors.initials: M
authors.lastname: Velimirovic
authors.affiliation: Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr Subotica 8, 11000 Belgrade, Serbia.
authors.forename: Marina
authors.initials: M
authors.lastname: Milenkovic
authors.affiliation: Institute of Clinical and Medical Biochemistry, School of Medicine, University of Belgrade, Pasterova 2, 11000 Belgrade, Serbia.
authors.forename: Tihomir
authors.initials: T
authors.lastname: Stojkovic
authors.affiliation: Institute of Histology and Embryology "Aleksandar Đ. Kostić", School of Medicine, University of Belgrade, Dr Subotica 8, 11000 Belgrade, Serbia.
authors.forename: Nela
authors.initials: N
authors.lastname: Puskas
authors.affiliation: Institute of Histology and Embryology "Aleksandar Đ. Kostić", School of Medicine, University of Belgrade, Dr Subotica 8, 11000 Belgrade, Serbia.
authors.forename: Ivan
authors.initials: I
authors.lastname: Zaletel
authors.affiliation: Department of Pathophysiology, Faculty of Medicine, University of Belgrade, Dr Subotica 8, 11000 Belgrade, Serbia.
authors.forename: Silvio R
authors.initials: SR
authors.lastname: De Luka
authors.affiliation: Institute of Meat Hygiene and Technology, Kacanskog 13, 11000 Belgrade, Serbia.
authors.forename: Sasa
authors.initials: S
authors.lastname: Jankovic
authors.affiliation: Institute of Meat Hygiene and Technology, Kacanskog 13, 11000 Belgrade, Serbia.
authors.forename: Srdjan
authors.initials: S
authors.lastname: Stefanovic
authors.affiliation: Institute of Pharmacology, Clinical Pharmacology and Toxicology, School of Medicine, University of Belgrade, Dr Subotica 8, 11000 Belgrade, Serbia.
authors.forename: Nina
authors.initials: N
authors.lastname: Japundzic-Zigon
authors.affiliation: Institute of Clinical and Medical Biochemistry, School of Medicine, University of Belgrade, Pasterova 2, 11000 Belgrade, Serbia.
authors.forename: Natasa D
authors.initials: ND
authors.lastname: Petronijevic
authors.affiliation: Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr Subotica 8, 11000 Belgrade, Serbia.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Trajkovic
authors.affiliation: Department of Pathophysiology, Faculty of Medicine, University of Belgrade, Dr Subotica 8, 11000 Belgrade, Serbia. Electronic address: alexander.m.trbovich@gmail.com.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Trbovich
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001219:Aspartate Aminotransferases / Q000097:blood; D003300:Copper / Q000378:metabolism; D003402:Creatine Kinase / Q000378:metabolism; D005786:Gene Expression Regulation; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D007249:Inflammation / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D000072179:Interleukin-1 Receptor-Like 1 Protein / Q000235:genetics / Q000378:metabolism*; D000067596:Interleukin-33 / Q000235:genetics / Q000378:metabolism*; D008274:Magnesium / Q000378:metabolism*; D008297:Male; D008345:Manganese / Q000378:metabolism; D008807:Mice, Inbred BALB C; D009132:Muscles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D012643:Selenium / Q000378:metabolism; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D000975:Antioxidants; C486189:Il1rl1 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D016212:Transforming Growth Factor beta; D008345:Manganese; D003300:Copper; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D001219:Aspartate Aminotransferases; D003402:Creatine Kinase; D005978:Glutathione; D012643:Selenium; D008274:Magnesium
keywords: Acute inflammation; Antioxidants; Cytokines; IL-33/ST2 pathway; Magnesium