Tumor necrosis factor-alpha-induced sickness behavior is impaired by central administration of an inhibitor of c-jun N-terminal kinase

Psychopharmacology (Berl). 2008 May;197(4):629-35. doi: 10.1007/s00213-008-1086-y. Epub 2008 Feb 12.


Rationale: 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.

Objectives: 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Appetite / drug effects*
  • Behavior, Animal / drug effects*
  • Body Weight / drug effects*
  • Brain / drug effects
  • Dose-Response Relationship, Drug
  • Exploratory Behavior
  • Injections, Intraventricular
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • Male
  • Mice
  • Motor Activity / drug effects*
  • Peptides / pharmacology*
  • Premedication
  • Signal Transduction / drug effects
  • Tumor Necrosis Factor-alpha / toxicity*


  • Peptides
  • Tumor Necrosis Factor-alpha
  • JNK Mitogen-Activated Protein Kinases
  • D-JNKI-1