The type 1 TNF receptor and its associated adapter protein, FAN, are required for TNFalpha-induced sickness behavior.
BACKGROUND
During the course of an infection, the pro-inflammatory cytokine tumor necrosis factor alpha (TNFalpha) acts in the brain to trigger development of behavioral responses, collectively termed sickness behavior. Biological activities of TNFalpha can be mediated by TNF receptor type 1 (TNF-R1) and type 2 (TNF-R2). TNFalpha activates neutral sphingomyelinase through the TNF-R1 adapter protein FAN (factor associated with neutral sphingomyelinase activation), but a behavioral role of FAN in the brain has never been reported.


OBJECTIVE
We hypothesized that TNFalpha-induced sickness behavior requires TNF-R1 and that FAN is a necessary component for this response.


METHODS
We determined the role of brain TNF-R1 in sickness behavior by administering an optimal amount of TNFalpha intracerebroventricularly (i.c.v., 50 ng/mouse) to wild-type (WT), TNF-R1-, TNF-R2-, and FAN-deficient mice. Sickness was assessed by decreased social exploration of a novel juvenile, induction of immobility, and loss of body weight.


RESULTS
TNF-R1-deficient mice were resistant to the sickness-inducing properties of i.c.v. TNFalpha, whereas both TNF-R2-deficient and WT mice were fully responsive. Furthermore, the complete absence of TNFalpha-induced sickness behavior in FAN-deficient mice provided in vivo evidence that FAN-dependent TNF-R1 signaling is critical for this central action of TNFalpha.


CONCLUSIONS
This is the first report to demonstrate that TNFalpha-induced sickness behavior is fully mediated by TNF-R1 and that the adaptor protein FAN is a necessary intracellular intermediate for sickness behavior.
Palin
Karine
K
Integrative Immunology and Behavior Program, Laboratory of Integrative Immunophysiology, Department of Animal Sciences, University of Illinois at Urbana-Champaign, 227 Edward R. Madigan Laboratory, 1201 West Gregory Drive, Urbana, IL 61801-3873, USA.
Bluthé
Rose-Marie
RM
McCusker
Robert H
RH
Levade
Thierry
T
Moos
Françoise
F
Dantzer
Robert
R
Kelley
Keith W
KW
D000818:Animals; D001522:Behavior, Animal; D005106:Exploratory Behavior; D007276:Injections, Intraventricular; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000378:metabolism*; D015431:Weight Loss
D047908:Intracellular Signaling Peptides and Proteins; C491112:Nsmaf protein, mouse; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha