Tumor necrosis factor-alpha-induced sickness behavior is impaired by central administration of an inhibitor of c-jun N-terminal kinase.
BACKGROUND
Tumor necrosis factor-alpha (TNFalpha) acts within the brain to induce sickness behavior, but the molecular mechanisms are still unknown. TNFalpha binding induces receptor trimerization, activation of c-Jun N-terminal kinase (JNK), and induction of downstream transcription factors.


OBJECTIVE
We hypothesized that TNFalpha-induced sickness behavior can be blocked by a novel JNK inhibitor.


METHODS
To test this idea, we used a bipartite protein consisting of a ten-amino-acid sequence of the trans-activating domain of the viral TAT protein (D-TAT) linked to a 19-amino-acid peptide that specifically inhibits JNK activation (D-JNKI-1). C57BL/6J mice were pre-treated intracerebroventricularly (i.c.v.) with D-JNKI-1 or the control peptide containing only the protein transduction domain, D-TAT. Mice were then injected centrally with an optimal amount of TNFalpha (50 ng/mouse) to induce sickness behavior. Sickness was assessed as a decrease in social exploration of a novel juvenile, an increase in duration of immobility and loss of body weight.


RESULTS
Pre-treatment with D-JNKI-1 (10 ng/mouse), but not D-TAT, significantly inhibited all three indices of sickness induced by central TNFalpha.


CONCLUSIONS
These findings demonstrate that D-JNKI-1 can abrogate TNFalpha-induced sickness behavior and suggest a potential therapeutic target for treating major depressive disorders that develop on a background of cytokine-induced sickness behavior.
Palin
K
K
Laboratory of Integrative Immunophysiology, Integrative Immunology and Behavior Program, Department of Animal Sciences, College of ACES, Urbana, IL 61801, USA.
McCusker
R H
RH
Strle
K
K
Moos
F
F
Dantzer
R
R
Kelley
K W
KW
D000818:Animals; D001066:Appetite / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects*; D001921:Brain / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior; D007276:Injections, Intraventricular; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D010455:Peptides / Q000494:pharmacology*; D011292:Premedication; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*
D010455:Peptides; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases; C478085:D-JNKI-1