title: Inhibition of vagally mediated immune-to-brain signaling by vanadyl sulfate speeds recovery from sickness.
abstract: To the ill patient with diabetes, the behavioral symptoms of sickness such as fatigue and apathy are debilitating and can prevent recuperation. Here we report that peripherally administered insulin-like growth factor 1 (IGF-1) attenuates LPS-dependent depression of social exploration (sickness) in nondiabetic (db/+) but not in diabetic (db/db) mice. We show that the insulin/IGF-1 mimetic vanadyl sulfate (VS) is effective at augmenting recovery from sickness in both db/+ and db/db mice. Specifically, peak illness was reached at 2 h for both VS and control animals injected with LPS, and VS mice recovered 50% faster than non-VS-treated animals. Examination of the mechanism of VS action in db/+ mice showed that VS paradoxically augmented peritoneal macrophage responsivity to LPS, increasing both peritoneal and ex vivo macrophage production of IL-1beta and IL-6 but not TNF-alpha. The effects of VS in promoting recovery from sickness were not restricted to LPS, because they were also observed after direct administration of IL-1beta. To explore the possibility that VS impairs immune-to-brain communication via vagal afferents, the vagally mediated satiety-inducing effects of cholecystokinin 8 were tested in db/+ mice. Cholecystokinin decreased food intake in saline-injected mice but not in VS-treated mice. VS also inhibited LPS-dependent up-regulation of IL-1beta and IL-6 mRNA in the brain, while increasing by 50% the cerebral expression of transcripts of the specific antagonist of IL-1 receptors IL-1RA and IL-1R2. Taken together, these data indicate that VS improves recovery from LPS-induced sickness by blocking vagally mediated immune-to-brain signaling and by up-regulating brain expression of IL-1beta antagonists.
authors.affiliation: Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Johnson
authors.forename: Jason C
authors.initials: JC
authors.lastname: O'Connor
authors.forename: Robert
authors.initials: R
authors.lastname: Dantzer
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Freund
mesh_terms: D000818:Animals; D001921:Brain / Q000502:physiology*; D002478:Cells, Cultured; D002766:Cholecystokinin / Q000494:pharmacology; D003920:Diabetes Mellitus / Q000188:drug therapy; D004435:Eating / Q000187:drug effects; D005106:Exploratory Behavior / Q000187:drug effects*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007107:Immune System / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology / Q000627:therapeutic use; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D012795:Sialoglycoproteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014630:Vagus Nerve / Q000378:metabolism*; D017968:Vanadium Compounds / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D007004:Hypoglycemic Agents; C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha; D017968:Vanadium Compounds; D007334:Insulin-Like Growth Factor I; C034028:vanadyl sulfate; D002766:Cholecystokinin