TNF gene cluster deletion abolishes lipopolysaccharide-mediated sensitization of the neonatal brain to hypoxic ischemic insult.
In the current study, we explored the role of TNF cluster cytokines on the lipopolysaccharide (LPS)-mediated, synergistic increase in brain injury after hypoxic ischemic insult in postnatal day 7 mice. Pretreatment with moderate doses of LPS (0.3 μg/g) resulted in particularly pronounced synergistic injury within 12 h. Systemic application of LPS alone resulted in a strong upregulation of inflammation-associated cytokines TNFα, LTβ, interleukin (IL) 1β, IL6, chemokines, such as CXCL1, and adhesion molecules E-Selectin, P-Selectin and intercellular adhesion molecule-1 (ICAM1), as well as a trend toward increased LTα levels in day 7 mouse forebrain. In addition, it was also associated with strong activation of brain blood vessel endothelia and local microglial cells. Here, deletion of the entire TNF gene cluster, removing TNFα, LTβ and LTα completely abolished endotoxin-mediated increase in the volume of cerebral infarct. Interestingly, the same deletion also prevented endothelial and microglial activation following application of LPS alone, suggesting the involvement of these cell types in bringing about the LPS-mediated sensitization to neonatal brain injury.
Perinatal Brain Repair Group, Centre for Perinatal Brain Protection and Repair, Institute of Women's Health, University College London, London, UK. g.kendall@ucl.ac.uk
Giles S
GS
Kendall
Mariya
M
Hristova
Mariya
M
Hirstova
Sigrun
S
Horn
Dimitra
D
Dafou
Alejandro
A
Acosta-Saltos
Beatriz
B
Almolda
Virginia
V
Zbarsky
Prakasham
P
Rumajogee
Heike
H
Heuer
Bernardo
B
Castellano
Klaus
K
Pfeffer
Sergei A
SA
Nedospasov
Donald M
DM
Peebles
Gennadij
G
Raivich
D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002544:Cerebral Infarction / Q000139:chemically induced / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004198:Disease Susceptibility; D004730:Endothelium, Vascular / Q000254:growth & development / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008233:Lymphotoxin-alpha / Q000235:genetics / Q000378:metabolism*; D053308:Lymphotoxin-beta / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism; D005810:Multigene Family; D012333:RNA, Messenger / Q000378:metabolism; D017384:Sequence Deletion; D012720:Severity of Illness Index; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
D015815:Cell Adhesion Molecules; D016207:Cytokines; D008070:Lipopolysaccharides; C505887:Ltb protein, mouse; D008233:Lymphotoxin-alpha; D053308:Lymphotoxin-beta; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha