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

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Abstract

Rationale

Tumor necrosis factor-α (TNFα) acts within the brain to induce sickness behavior, but the molecular mechanisms are still unknown. TNFα binding induces receptor trimerization, activation of c-Jun N-terminal kinase (JNK), and induction of downstream transcription factors.

Objectives

We hypothesized that TNFα-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 TNFα (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 TNFα.

Conclusions

These findings demonstrate that D-JNKI-1 can abrogate TNFα-induced sickness behavior and suggest a potential therapeutic target for treating major depressive disorders that develop on a background of cytokine-induced sickness behavior.

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References

  • Becker-Hapak M, McAllister SS, Dowdy SF (2001) TAT-mediated protein transduction into mammalian cells. Methods 24:247–256

    Article  PubMed  CAS  Google Scholar 

  • Bette M, Kaut O, Schafer MK, Weihe E (2003) Constitutive expression of p55TNFR mRNA and mitogen-specific up-regulation of TNF alpha and p75TNFR mRNA in mouse brain. J Comp Neurol 465:417–430

    Article  PubMed  CAS  Google Scholar 

  • Bluthe RM, Dantzer R, Kelley KW (1991) Interleukin-1 mediates behavioural but not metabolic effects of tumor necrosis factor alpha in mice. Eur J Pharmacol 209:281–283

    Article  PubMed  CAS  Google Scholar 

  • Bluthe RM, Pawlowski M, Suarez S, Parnet P, Pittman Q, Kelley KW, Dantzer R (1994) Synergy between tumor necrosis factor alpha and interleukin-1 in the induction of sickness behavior in mice. Psychoneuroendocrinology 19:197–207

    Article  PubMed  CAS  Google Scholar 

  • Bluthe RM, Laye S, Michaud B, Combe C, Dantzer R, Parnet P (2000) Role of interleukin-1beta and tumour necrosis factor-alpha in lipopolysaccharide-induced sickness behaviour: a study with interleukin-1 type I receptor-deficient mice. Eur J Neurosci 12:4447–4456

    Article  PubMed  CAS  Google Scholar 

  • Bluthe RM, Kelley KW, Dantzer R (2006) Effects of insulin-like growth factor-I on cytokine-induced sickness behavior in mice. Brain Behav Immun 20:57–63

    Article  PubMed  CAS  Google Scholar 

  • Borsello T, Clarke PG, Hirt L, Vercelli A, Repici M, Schorderet DF, Bogousslavsky J, Bonny C (2003) A peptide inhibitor of c-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia. Nat Med 9:1180–1186

    Article  PubMed  CAS  Google Scholar 

  • Bubici C, Papa S, Pham CG, Zazzeroni F, Franzoso G (2004) NF-kappaB and JNK: an intricate affair. Cell Cycle 3:1524–1529

    PubMed  CAS  Google Scholar 

  • Chauhan A, Tikoo A, Kapur AK, Singh M (2007) The taming of the cell penetrating domain of the HIV Tat: myths and realities. J Control Release 117:148–162

    Article  PubMed  CAS  Google Scholar 

  • Crestani F, Seguy F, Dantzer R (1991) Behavioural effects of peripherally injected interleukin-1: role of prostaglandins. Brain Res 542:330–335

    Article  PubMed  CAS  Google Scholar 

  • Dantzer R, Kelley KW (2007) Twenty years of research on cytokine-induced sickness behavior. Brain Behav Immun 21:153–160

    Article  PubMed  CAS  Google Scholar 

  • Dantzer R, Bluthe RM, Castanon N, Kelley KW, Konsman JP, Laye S, Lestage J, Parnet P (2006) Cytokines, sickness behavior and depression. In: Ader R (ed) Psychoneuroimmunology, Fourth Edition. Academic Press, New York, NY, pp 281–318

    Google Scholar 

  • Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW (2008a) From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9:46–56

    Article  PubMed  CAS  Google Scholar 

  • Dantzer R, Capuron L, Irwin MR, Miller AH, Ollat H, Hugh Perry V, Rousey S, Yirmiya R (2008b) Identification and treatment of symptoms associated with inflammation in medically ill patients. Psychoneuroendocrinology 33:18–29

    Article  PubMed  Google Scholar 

  • Figiel I, Dzwonek K (2007) TNFalpha and TNF receptor 1 expression in the mixed neuronal-glial cultures of hippocampal dentate gyrus exposed to glutamate or trimethyltin. Brain Res 1131:17–28

    Article  PubMed  CAS  Google Scholar 

  • Fiore M, Probert L, Kollias G, Akassoglou K, Alleva E, Aloe L (1996) Neurobehavioral alterations in developing transgenic mice expressing TNF-alpha in the brain. Brain Behav Immun 10:126–138

    Article  PubMed  CAS  Google Scholar 

  • Fiore M, Alleva E, Probert L, Kollias G, Angelucci F, Aloe L (1998) Exploratory and displacement behavior in transgenic mice expressing high levels of brain TNF-alpha. Physiol Behav 63:571–576

    Article  PubMed  CAS  Google Scholar 

  • Gustafsson AB, Gottlieb RA, Granville DJ (2005) TAT-mediated protein transduction: delivering biologically active proteins to the heart. Methods Mol Med 112:81–90

    PubMed  CAS  Google Scholar 

  • Kuan CY, Burke RE (2005) Targeting the JNK signaling pathway for stroke and Parkinson’s diseases therapy. Curr Drug Targets CNS Neurol Disord 4:63–67

    Article  PubMed  CAS  Google Scholar 

  • Lanquillon S, Krieg JC, Bening-Abu-Shach U, Vedder H (2000) Cytokine production and treatment response in major depressive disorder. Neuropsychopharmacology 22:370–379

    Article  PubMed  CAS  Google Scholar 

  • Lotocki G, de Rivero Vaccari JP, Perez ER, Alonso OF, Curbelo K, Keane RW, Dietrich WD (2006) Therapeutic hypothermia modulates TNFR1 signaling in the traumatized brain via early transient activation of the JNK pathway and suppression of XIAP cleavage. Eur J Neurosci 24:2283–2290

    Article  PubMed  Google Scholar 

  • MacEwan DJ (2002) TNF ligands and receptors—a matter of life and death. Br J Pharmacol 135:855–875

    Article  PubMed  CAS  Google Scholar 

  • Manning AM, Davis RJ (2003) Targeting JNK for therapeutic benefit: from junk to gold? Nat Rev Drug Discov 2:554–565

    Article  PubMed  CAS  Google Scholar 

  • McCusker RH, Strle K, Broussard SR, Dantzer R, Bluthé RM, Kelley KW (2006) Crosstalk between insulin-like growth factors and pro-inflammatory cytokines. In: Adler R, Dantzer R, Glaser R, Heijnen C, Irwin M, Padgett D, Sheridan J (eds) Psychoneuroimmunology. Academic Press, New York, pp 171–191

    Google Scholar 

  • Medeiros R, Prediger RD, Passos GF, Pandolfo P, Duarte FS, Franco JL, Dafre AL, Di Giunta G, Figueiredo CP, Takahashi RN, Campos MM, Calixto JB (2007) Connecting TNF-alpha signaling pathways to iNOS expression in a mouse model of Alzheimer’s disease: relevance for the behavioral and synaptic deficits induced by amyloid beta protein. J Neurosci 27:5394–5404

    Article  PubMed  CAS  Google Scholar 

  • Minogue AM, Schmid AW, Fogarty MP, Moore AC, Campbell VA, Herron CE, Lynch MA (2003) Activation of the c-Jun N-terminal kinase signaling cascade mediates the effect of amyloid-beta on long term potentiation and cell death in hippocampus: a role for interleukin-1beta? J Biol Chem 278:27971–27980

    Article  PubMed  CAS  Google Scholar 

  • Moraes JC, Amaral ME, Picardi PK, Calegari VC, Romanatto T, Bermudez-Echeverry M, Chiavegatto S, Saad MJ, Velloso LA (2006) Inducible-NOS but not neuronal-NOS participate in the acute effect of TNF-alpha on hypothalamic insulin-dependent inhibition of food intake. FEBS Lett 580:4625–4631

    Article  PubMed  CAS  Google Scholar 

  • Nadjar A, Bluthe RM, May MJ, Dantzer R, Parnet P (2005) Inactivation of the cerebral NFkappaB pathway inhibits interleukin-1beta-induced sickness behavior and c-Fos expression in various brain nuclei. Neuropsychopharmacology 30:1492–1499

    Article  PubMed  CAS  Google Scholar 

  • O’Connor JC, Lawson MA, André C, Moreau M, Lestage J, Cantanon N, Kelley KW, Dantzer R (2008a) Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice. Mol. Psychiat (in press) Jan 15 DOI 10.1038/sj.mp.4002148

  • O’Connor JC, McCusker RH, Strle K, Johnson RW, Dantzer R, Kelley KW (2008b) Regulation of IGF-I function by proinflammatory cytokines: At the interface of immunology and endocrinology. Cell. Immunol (in press)

  • Palin K, Bluthe RM, McCusker RH, Moos F, Dantzer R, Kelley KW (2007) TNFalpha-induced sickness behavior in mice with functional 55 kD TNF receptors is blocked by central IGF-I. J Neuroimmunol 187:55–60

    Article  PubMed  CAS  Google Scholar 

  • Paxinos G, Franklin KBJ (2001) The mouse brain in stereotaxic coordinates, second edition (Deluxe) edn. Academic Press, New York, NY

    Google Scholar 

  • Pradillo JM, Romera C, Hurtado O, Cardenas A, Moro MA, Leza JC, Davalos A, Castillo J, Lorenzo P, Lizasoain I (2005) TNFR1 upregulation mediates tolerance after brain ischemic preconditioning. J Cereb Blood Flow Metab 25:193–203

    Article  PubMed  CAS  Google Scholar 

  • Repici M, Borsello T (2006) JNK pathway as therapeutic target to prevent degeneration in the central nervous system. Adv Exp Med Biol 588:145–155

    Article  PubMed  Google Scholar 

  • Repici M, Centeno C, Tomasi S, Forloni G, Bonny C, Vercelli A, Borsello T (2007) Time-course of c-Jun N-terminal kinase activation after cerebral ischemia and effect of D-JNKI1 on c-Jun and caspase-3 activation. Neuroscience 150:40–49

    Article  PubMed  CAS  Google Scholar 

  • Strle K, Broussard SR, McCusker RH, Shen WH, LeCleir JM, Johnson RW, Freund GG, Dantzer R, Kelley KW (2006) C-jun N-terminal kinase mediates tumor necrosis factor-alpha suppression of differentiation in myoblasts. Endocrinology 147:4363–4373

    Article  PubMed  CAS  Google Scholar 

  • Tilstra J, Rehman KK, Hennon T, Plevy SE, Clemens P, Robbins PD (2007) Protein transduction: identification, characterization and optimization. Biochem Soc Trans 35:811–815

    Article  PubMed  CAS  Google Scholar 

  • Vandenabeele P, Declercq W, Beyaert R, Fiers W (1995) Two tumour necrosis factor receptors: structure and function. Trends Cell Biol 5:392–399

    Article  PubMed  CAS  Google Scholar 

  • Wadia JS, Dowdy SF (2005) Transmembrane delivery of protein and peptide drugs by TAT-mediated transduction in the treatment of cancer. Adv Drug Deliv Rev 57:579–596

    Article  PubMed  CAS  Google Scholar 

  • Waetzig V, Czeloth K, Hidding U, Mielke K, Kanzow M, Brecht S, Goetz M, Lucius R, Herdegen T, Hanisch UK (2005) c-Jun N-terminal kinases (JNKs) mediate pro-inflammatory actions of microglia. Glia 50:235–246

    Article  PubMed  Google Scholar 

  • Yang L, Lindholm K, Konishi Y, Li R, Shen Y (2002) Target depletion of distinct tumor necrosis factor receptor subtypes reveals hippocampal neuron death and survival through different signal transduction pathways. J Neurosci 22:3025–3032

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This research was supported by grants from the National Institutes of Health (NIH) to K.W.K. (MH51569 and AG029573) and R.D. (MH071349 and MH079829). The authors do not have a financial relationship with sponsoring organizations.

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Authors and Affiliations

  1. Laboratory of Integrative Immunophysiology, Integrative Immunology and Behavior Program, Department of Animal Sciences, College of ACES, Urbana, IL, 61801, USA

    K. Palin, R. H. McCusker, K. Strle, R. Dantzer & K. W. Kelley

  2. Laboratoire Psynugen, CNRS, UMR5226, University Bordeaux, INRA, UMR1286 INRA, 146 rue Léo Saignat, Bordeaux, F-33077, France

    F. Moos

  3. Department of Pathology, College of Medicine, University of Illinois, Urbana, IL, 61801, USA

    R. Dantzer & K. W. Kelley

  4. Laboratory of Integrative Immunophysiology, Integrative Immunology and Behavior Program, 227 Edward R. Madigan Laboratory, University of Illinois at Urbana-Champaign, 1201 West Gregory Drive, Urbana, IL, 61801-3873, USA

    K. W. Kelley

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  1. K. Palin
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  2. R. H. McCusker
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  3. K. Strle
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  4. F. Moos
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  5. R. Dantzer
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  6. K. W. Kelley
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Correspondence to K. W. Kelley.

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Palin, K., McCusker, R.H., Strle, K. et al. Tumor necrosis factor-α-induced sickness behavior is impaired by central administration of an inhibitor of c-jun N-terminal kinase. Psychopharmacology 197, 629–635 (2008). https://doi.org/10.1007/s00213-008-1086-y

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  • DOI: https://doi.org/10.1007/s00213-008-1086-y

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