IL-6 deficiency causes enhanced pathology in Twitcher (globoid cell leukodystrophy) mice.
The expression of IL-6 is greatly enhanced in the twitcher mouse (S. M. LeVine and D. C. Brown, 1997, J. Neuroimmunol. 73, 47-56), which is an authentic animal model of globoid cell leukodystrophy (Krabbe's disease). In order to investigate the role of IL-6 in this disease, twitcher/IL-6-deficient mice were generated and the pathology was compared between them and regular twitcher mice. Twitcher/IL-6-deficient mice had a more severe disease than regular twitcher mice: they had an earlier onset day of twitching, a greater number of PAS-positive cells, a greater susceptibility to LPS, an exaggerated gliotic response around some vessels, an elevated level of TNF-alpha, and a compromised blood-brain barrier, which was evaluated by three independent measures. This latter finding indicates that IL-6 plays a role in maintaining the integrity of the BBB, and it raises the possibility that IL-6 functions in a similar manner in other diseases of the CNS. LPS was found to greatly shorten the life of twitcher and twitcher/IL-6-deficient mice compared to genotyped-matched saline-injected mice. This result indicates that a proinflammatory condition can exacerbate an underlying CNS pathology, which could help explain why some leukodystrophy patients display their initial symptoms following a fever or blow to the head.
Pedchenko
T V
TV
Department of Molecular and Integrative Physiology and the Mental Retardation and Human Development Center, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, Kansas, 66160, USA.
LeVine
S M
SM
D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000473:pathology*; D003433:Crosses, Genetic; D018450:Disease Progression; D004926:Escherichia coli; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D037102:Lectins; D007965:Leukodystrophy, Globoid Cell / Q000473:pathology* / Q000503:physiopathology; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D009043:Motor Activity; D004676:Myelin Basic Protein / Q000032:analysis; D012249:Rhombencephalon / Q000737:chemistry / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D005904:Glial Fibrillary Acidic Protein; D015850:Interleukin-6; D037102:Lectins; D008070:Lipopolysaccharides; D004676:Myelin Basic Protein; D014409:Tumor Necrosis Factor-alpha