Role of interleukin-6 in lipopolysaccharide-induced brain injury and behavioral dysfunction in neonatal rats.
There are increasing data in support of the hypothesis that inflammatory cytokines are involved in neonatal white matter damage. Despite extensive study of the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1beta, the role of interleukin-6 in the development of white matter damage is largely unknown. In the present study, the role(s) of interleukin-6 in mediating lipopolysaccharide-induced brain injury and behavioral changes was investigated by the intracerebral injection of lipopolysaccharide with interleukin-6 neutralizing antibody in the 5-day-old rat brain. Brain injury was examined in brain sections at postnatal day 8 and postnatal day 21. Behavioral tests including righting reflex, wire hanging maneuver, cliff avoidance, locomotor activity, gait analysis, responses in the elevated plus-maze and passive avoidance were performed from postnatal day 3 to postnatal day 21. Changes in astroglia, microglia and oligodendrocytes were studied using immunohistochemistry in the postnatal day 21 rat brain. Our results show that interleukin-6 antibody attenuated lipopolysaccharide-induced brain lateral ventricle dilation and improved neurobehavioral performance. Interleukin-6 antibody also suppressed lipopolysaccharide-induced astrogliosis and microglial activation, and increased the number of oligodendrocytes in white matter. However, no changes of tumor necrosis factor-alpha and interleukin-1beta were detected. In contrast, no histopathological changes and glial activation were observed in rats injected with only interleukin-6. The present study indicates that the contribution to brain injury by interleukin-6 depends on its interaction with other lipopolysaccharide-induced agents and not on interleukin-6 alone.
Pang
Y
Y
Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA.
Fan
L-W
LW
Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA.
Zheng
B
B
Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA.
Cai
Z
Z
Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA.
Rhodes
P G
PG
Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA. Electronic address: prhodes@ped.umsmed.edu.
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000008:administration & dosage; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D001930:Brain Injuries / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology*; D002452:Cell Count / Q000379:methods; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D007150:Immunohistochemistry / Q000379:methods; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000502:physiology*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000906:Antibodies; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha