title: Tumor necrosis factor-inducible gene 6 protein: A novel neuroprotective factor against inflammation-induced developmental brain injury.
abstract: Inflammation is an important factor contributing to developmental brain injury in preterm infants. Although tumor necrosis factor-inducible gene 6 protein (TSG-6) has immunomodulatory effects in several inflammatory conditions of adult animals, nothing is currently known about the role of TSG-6 in the developing brain, its impact on perinatal inflammation and its therapeutic potential. The aim of the current work was 1) to characterize the developmental expression of TSG-6 in the newborn rat brain, 2) to evaluate the impact of LPS exposure on TSG-6 expression and 3) to assess the therapeutic potential of exogenous TSG-6 administration. Brain hemispheres of healthy Wistar rats (postnatal day 1-postnatal day 15 (P1-P15)) were evaluated with regard to the physiological expression of TSG-6. LPS-treated rats (0.25mg/kg LPS i.p. on P3) were analyzed for inflammation-induced changes in TSG-6 and cytokine expression. To evaluate whether exogenous recombinant human (rh)TSG-6 affects inflammation-induced brain injury, newborn Wistar rats, exposed to LPS on P3, were treated with rhTSG-6 i.p. (four repetitive doses of 2.25mg/kg every 12h, first dose 3h before LPS injection). PCR, Western blotting and multiplex ELISA were performed according to standard protocols. TSG-6 is physiologically expressed in the developing brain with a linear increase in expression from P1 to P15 at the mRNA level. At P6, regional differences in TSG-6 expression in the cortex, thalamus and striatum were detected at mRNA and protein level. Furthermore, TSG-6 gene expression was significantly increased by inflammation (induced by LPS treatment). Combined treatment with LPS and TSG-6 vs. LPS exposure alone, resulted in significant down-regulation of cleaved caspase-3, a marker of apoptosis and neuronal plasticity. In addition, several inflammatory serum markers were decreased after TSG-6 treatment. Finally, TSG-6 is physiologically expressed in the developing brain. Changes of TSG-6 expression associated with inflammation suggest a role of TSG-6 in neuroinflammation. Reduction of cleaved caspase-3 by TSG-6 treatment demonstrates the putative neuroprotective potential of exogenous TSG-6 administration in inflammation-induced developmental brain injury.
authors.affiliation: Dept. of Pediatrics I-Neonatology, University Hospital Essen, University Duisburg-Essen, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Bertling
authors.affiliation: Dept. of Pediatrics I-Neonatology, University Hospital Essen, University Duisburg-Essen, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Bendix
authors.affiliation: Dept. of Pediatrics I-Neonatology, University Hospital Essen, University Duisburg-Essen, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Drommelschmidt
authors.affiliation: Dept. of Microbiology, New York University School of Medicine, New York, USA.
authors.forename: H G
authors.initials: HG
authors.lastname: Wisniewski
authors.affiliation: Dept. of Pediatrics I-Neonatology, University Hospital Essen, University Duisburg-Essen, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Felderhoff-Mueser
authors.affiliation: Dept. of Pediatrics I-Neonatology, University Hospital Essen, University Duisburg-Essen, Germany; Technical University Munich, Germany; Children's Hospital Passau, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Keller
authors.affiliation: Dept. of Pediatrics I-Neonatology, University Hospital Essen, University Duisburg-Essen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Prager
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000254:growth & development; D053148:Caspase 3 / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis; D004660:Encephalitis / Q000139:chemically induced / Q000235:genetics*; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity; D009473:Neuronal Plasticity / Q000187:drug effects; D000066829:Neuroprotection; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D015815:Cell Adhesion Molecules; D016207:Cytokines; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D011994:Recombinant Proteins; C072273:TNFAIP6 protein, human; C513056:Tnfaip6 protein, rat; C505410:Casp3 protein, rat; D053148:Caspase 3
keywords: Inflammation; Neonatal brain damage; TNFAIP-6; TSG-6; Tumor necrosis factor-inducible gene 6 protein