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.
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.
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Pedchenko
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LeVine
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