Skip to main content

Advertisement

SpringerLink
Log in

AChE and RACK1 Promote the Anti-Inflammatory Properties of Fluoxetine

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Selective serotonin reuptake inhibitors (SSRIs) show anti-inflammatory effects, suggesting a possible interaction with both Toll-like-receptor 4 (TLR4) responses and cholinergic signaling through as yet unclear molecular mechanism(s). Our results of structural modeling support the concept that the antidepressant fluoxetine physically interacts with the TLR4–myeloid differentiation factor-2 complex at the same site as bacterial lipopolysaccharide (LPS). We also demonstrate reduced LPS-induced pro-inflammatory interleukin-6 and tumor necrosis factor alpha in human peripheral blood mononuclear cells preincubated with fluoxetine. Furthermore, we show that fluoxetine intercepts the LPS-induced decreases in intracellular acetylcholinesterase (AChE-S) and that AChE-S interacts with the nuclear factor kappa B (NFκB)-activating intracellular receptor for activated C kinase 1 (RACK1). This interaction may prevent NFκB activation by residual RACK1 and its interacting protein kinase PKCβII. Our findings attribute the anti-inflammatory properties of SSRI to surface membrane interference with leukocyte TLR4 activation accompanied by intracellular limitation of pathogen-inducible changes in AChE-S, RACK1, and PKCβII.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Adams DR, Ron D, Kiely PA (2011) RACK1, a multifaceted scaffolding protein: structure and function. Cell Commun Signal 9:22

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Akashi-Takamura S, Miyake K (2008) TLR accessory molecules. Curr Opin Immunol 20:420–425

    Article  CAS  PubMed  Google Scholar 

  • Aksoy E, Amraoui Z, Goriely S, Goldman M, Willems F (2002) Critical role of protein kinase C epsilon for lipopolysaccharide-induced IL-12 synthesis in monocyte-derived dendritic cells. Eur J Immunol 32:3040–3049

    Article  CAS  PubMed  Google Scholar 

  • Bertrand C, Bonafos B, Tremblay M, Ferry A, Chatonnet A (2008) Effect of fluoxetine on neuromuscular function in acetylcholinesterase (AChE) knockout mice. Chem Biol Interact 175:113–114

    Article  CAS  PubMed  Google Scholar 

  • Bird RJ, Baillie GS, Yarwood SJ (2010) Interaction with receptor for activated C-kinase 1 (RACK1) sensitizes the phosphodiesterase PDE4D5 towards hydrolysis of cAMP and activation by protein kinase C. Biochem J 432:207–216

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Birikh KR, Sklan EH, Shoham S, Soreq H (2003) Interaction of “readthrough” acetylcholinesterase with RACK1 and PKCbeta II correlates with intensified fear-induced conflict behavior. Proc Natl Acad Sci U S A 100:283–288

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, Wang H, Abumrad N, Eaton JW, Tracey KJ (2000) Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405:458–462

    Article  CAS  PubMed  Google Scholar 

  • Brandon NJ, Uren JM, Kittler JT, Wang H, Olsen R, Parker PJ, Moss SJ (1999) Subunit-specific association of protein kinase C and the receptor for activated C kinase with GABA type A receptors. J Neurosci 19:9228–9234

    CAS  PubMed  Google Scholar 

  • Brandon NJ, Jovanovic JN, Smart TG, Moss SJ (2002) Receptor for activated C kinase-1 facilitates protein kinase C-dependent phosphorylation and functional modulation of GABA(A) receptors with the activation of G-protein-coupled receptors. J Neurosci 22:6353–6361

    CAS  PubMed  Google Scholar 

  • Charles HC, Lazeyras F, Krishnan KR, Boyko OB, Payne M, Moore D (1994) Brain choline in depression: in vivo detection of potential pharmacodynamic effects of antidepressant therapy using hydrogen localized spectroscopy. Prog Neuropsychopharmacol Biol Psychiatry 18:1121–1127

    Article  CAS  PubMed  Google Scholar 

  • Chen CC, Wang JK, Lin SB (1998) Antisense oligonucleotides targeting protein kinase C-alpha, -beta I, or -delta but not -eta inhibit lipopolysaccharide-induced nitric oxide synthase expression in RAW 264.7 macrophages: involvement of a nuclear factor kappa B-dependent mechanism. J Immunol 161:6206–6214

    CAS  PubMed  Google Scholar 

  • Chen YW, Rada PV, Butzler BP, Leibowitz SF, Hoebel BG (2012) Corticotropin-releasing factor in the nucleus accumbens shell induces swim depression, anxiety, and anhedonia along with changes in local dopamine/acetylcholine balance. Neuroscience 206:155–166

    Article  CAS  PubMed  Google Scholar 

  • Coudronniere N, Villalba M, Englund N, Altman A (2000) NF-kappa B activation induced by T cell receptor/CD28 costimulation is mediated by protein kinase C-theta. Proc Natl Acad Sci U S A 97:3394–3399

    CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Del Arco A, Segovia G, Garrido P, de Blas M, Mora F (2007) Stress, prefrontal cortex and environmental enrichment: studies on dopamine and acetylcholine release and working memory performance in rats. Behav Brain Res 176:267–273

    Article  PubMed  Google Scholar 

  • Dvir H, Harel M, Bon S, Liu WQ, Vidal M, Garbay C, Sussman JL, Massoulie J, Silman I (2004) The synaptic acetylcholinesterase tetramer assembles around a polyproline II helix. EMBO J 23:4394–4405

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Dvir H, Silman I, Harel M, Rosenberry TL, Sussman JL (2010) Acetylcholinesterase: from 3D structure to function. Chem Biol Interact 187:10–22

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Fancy DA, Kodadek T (1999) Chemistry for the analysis of protein-protein interactions: rapid and efficient cross-linking triggered by long wavelength light. Proc Natl Acad Sci U S A 96:6020–6024

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Garate I, Garcia-Bueno B, Madrigal JL, Bravo L, Berrocoso E, Caso JR, Mico JA, Leza JC (2011) Origin and consequences of brain Toll-like receptor 4 pathway stimulation in an experimental model of depression. J Neuroinflammation 8:151

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gilboa-Geffen A, Hartmann G, Soreq H (2012) Stressing hematopoiesis and immunity: an acetylcholinesterase window into nervous and immune system interactions. Front Mol Neurosci 5:30

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Grisaru D, Pick M, Perry C, Sklan EH, Almog R, Goldberg I, Naparstek E, Lessing JB, Soreq H, Deutsch V (2006) Hydrolytic and nonenzymatic functions of acetylcholinesterase comodulate hemopoietic stress responses. J Immunol 176:27–35

    Article  CAS  PubMed  Google Scholar 

  • Guex N, Peitsch MC (1997) SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling. Electrophoresis 18:2714–2723

    Article  CAS  PubMed  Google Scholar 

  • He DY, Neasta J, Ron D (2010) Epigenetic regulation of BDNF expression via the scaffolding protein RACK1. J Biol Chem 285:19043–19050

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hutchinson MR, Loram LC, Zhang Y, Shridhar M, Rezvani N, Berkelhammer D, Phipps S, Foster PS, Landgraf K, Falke JJ et al (2010) Evidence that tricyclic small molecules may possess toll-like receptor and myeloid differentiation protein 2 activity. Neuroscience 168:551–563

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Irwin JJ, Sterling T, Mysinger MM, Bolstad ES, Coleman RG (2012) ZINC: a free tool to discover chemistry for biology. J Chem Inf Model 52:1757–1768

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Iwamoto T, Hagiwara M, Hidaka H, Isomura T, Kioussis D, Nakashima I (1992) Accelerated proliferation and interleukin-2 production of thymocytes by stimulation of soluble anti-CD3 monoclonal antibody in transgenic mice carrying a rabbit protein kinase C alpha. J Biol Chem 267:18644–18648

    CAS  PubMed  Google Scholar 

  • Kagan JC, Medzhitov R (2006) Phosphoinositide-mediated adaptor recruitment controls Toll-like receptor signaling. Cell 125:943–955

    Article  CAS  PubMed  Google Scholar 

  • Kawai T, Akira S (2010) The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 11:373–384

    Article  CAS  PubMed  Google Scholar 

  • Koran LM, Cain JW, Dominguez RA, Rush AJ, Thiemann S (1996) Are fluoxetine plasma levels related to outcome in obsessive-compulsive disorder? Am J Psychiatry 153:1450–1454

    CAS  PubMed  Google Scholar 

  • Leitges M, Schmedt C, Guinamard R, Davoust J, Schaal S, Stabel S, Tarakhovsky A (1996) Immunodeficiency in protein kinase cbeta-deficient mice. Science 273:788–791

    Article  CAS  PubMed  Google Scholar 

  • Leonard BE (2010) The concept of depression as a dysfunction of the immune system. Curr Immunol Rev 6:205–212

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Leppanen T, Jalonen U, Kankaanranta H, Tuominen R, Moilanen E (2008) Inhibition of protein kinase C beta II downregulates tristetraprolin expression in activated macrophages. Inflamm Res 57:230–240

    Article  CAS  PubMed  Google Scholar 

  • Liu D, Wang Z, Liu S, Wang F, Zhao S, Hao A (2011) Anti-inflammatory effects of fluoxetine in lipopolysaccharide(LPS)-stimulated microglial cells. Neuropharmacology 61:592–599

    Article  CAS  PubMed  Google Scholar 

  • Loegering DJ, Lennartz MR (2011) Protein kinase C and toll-like receptor signaling. Enzym Res 2011:537821

    Article  Google Scholar 

  • Maggi L, Palma E, Miledi R, Eusebi F (1998) Effects of fluoxetine on wild and mutant neuronal alpha 7 nicotinic receptors. Mol Psychiatry 3:350–355

    Article  CAS  PubMed  Google Scholar 

  • Mineur YS, Obayemi A, Wigestrand MB, Fote GM, Calarco CA, Li AM, Picciotto MR (2013) Cholinergic signaling in the hippocampus regulates social stress resilience and anxiety- and depression-like behavior. Proc Natl Acad Sci U S A 110:3573–3578

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Mochly-Rosen D, Khaner H, Lopez J, Smith BL (1991) Intracellular receptors for activated protein kinase C. Identification of a binding site for the enzyme. J Biol Chem 266:14866–14868

    CAS  PubMed  Google Scholar 

  • Nilsson J, Sengupta J, Frank J, Nissen P (2004) Regulation of eukaryotic translation by the RACK1 protein: a platform for signalling molecules on the ribosome. EMBO Rep 5:1137–1141

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • O’Brien SM, Scully P, Fitzgerald P, Scott LV, Dinan TG (2007) Plasma cytokine profiles in depressed patients who fail to respond to selective serotonin reuptake inhibitor therapy. J Psychiatr Res 41:326–331

    Article  PubMed  Google Scholar 

  • Ofek K, Schoknecht K, Melamed-Book N, Heinemann U, Friedman A, Soreq H (2012) Fluoxetine induces vasodilatation of cerebral arterioles by co-modulating NO/muscarinic signalling. J Cell Mol Med 16:2736–2744

    Article  CAS  PubMed  Google Scholar 

  • Park BS, Song DH, Kim HM, Choi BS, Lee H, Lee JO (2009) The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex. Nature 458:1191–1195

    Article  CAS  PubMed  Google Scholar 

  • Perry C, Pick M, Podoly E, Gilboa-Geffen A, Zimmerman G, Sklan EH, Ben-Shaul Y, Diamant S, Soreq H (2007) Acetylcholinesterase/C terminal binding protein interactions modify Ikaros functions, causing T lymphopenia. Leukemia 21:1472–1480

    Article  CAS  PubMed  Google Scholar 

  • Pick M, Perry C, Lapidot T, Guimaraes-Sternberg C, Naparstek E, Deutsch V, Soreq H (2006) Stress-induced cholinergic signaling promotes inflammation-associated thrombopoiesis. Blood 107:3397–3406

    Article  CAS  PubMed  Google Scholar 

  • Pierce BG, Hourai Y, Weng Z (2011) Accelerating protein docking in ZDOCK using an advanced 3D convolution library. PLoS One 6:e24657

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Prado VF, Roy A, Kolisnyk B, Gros R, Prado MA (2013) Regulation of cholinergic activity by the vesicular acetylcholine transporter. Biochem J 450:265–274

    Article  CAS  PubMed  Google Scholar 

  • Ron D, Chen CH, Caldwell J, Jamieson L, Orr E, Mochly-Rosen D (1994) Cloning of an intracellular receptor for protein kinase C: a homolog of the beta subunit of G proteins. Proc Natl Acad Sci U S A 91:839–843

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ron D, Jiang Z, Yao L, Vagts A, Diamond I, Gordon A (1999) Coordinated movement of RACK1 with activated betaIIPKC. J Biol Chem 274:27039–27046

    Article  CAS  PubMed  Google Scholar 

  • Rosas-Ballina M, Tracey KJ (2009) The neurology of the immune system: neural reflexes regulate immunity. Neuron 64:28–32

    Article  CAS  PubMed  Google Scholar 

  • Ruiz Carrillo D, Chandrasekaran R, Nilsson M, Cornvik T, Liew CW, Tan SM, Lescar J (2012) Structure of human Rack1 protein at a resolution of 2.45 A. Acta Crystallogr Sect F Struct Biol Cryst Commun 68:867–872

    Article  CAS  PubMed  Google Scholar 

  • Russo P, Taly A (2012) alpha7-Nicotinic acetylcholine receptors: an old actor for new different roles. Curr Drug Targets 13:574–578

    Article  CAS  PubMed  Google Scholar 

  • Sacre S, Medghalchi M, Gregory B, Brennan F, Williams R (2010) Fluoxetine and citalopram exhibit potent antiinflammatory activity in human and murine models of rheumatoid arthritis and inhibit toll-like receptors. Arthritis Rheum 62:683–693

    Article  CAS  PubMed  Google Scholar 

  • Saijo K, Schmedt C, Su IH, Karasuyama H, Lowell CA, Reth M, Adachi T, Patke A, Santana A, Tarakhovsky A (2003) Essential role of Src-family protein tyrosine kinases in NF-kappaB activation during B cell development. Nat Immunol 4:274–279

    Article  CAS  PubMed  Google Scholar 

  • Saito N, Kikkawa U, Nishizuka Y (2002) The family of protein kinase C and membrane lipid mediators. J Diabetes Complications 16:4–8

    Article  PubMed  Google Scholar 

  • Sands WA, Bulut V, Severn A, Xu D, Liew FY (1994) Inhibition of nitric oxide synthesis by interleukin-4 may involve inhibiting the activation of protein kinase C epsilon. Eur J Immunol 24:2345–2350

    Article  CAS  PubMed  Google Scholar 

  • Sanner MF (1999) Python: a programming language for software integration and development. J Mol Graph Model 17:57–61

    CAS  PubMed  Google Scholar 

  • Santaguida PL, MacQueen G, Keshavarz H, Levine M, Beyene J, Raina P (2012) Treatment for depression after unsatisfactory response to SSRIs. Agency for Healthcare Research and Quality, Rockville

    Google Scholar 

  • Shaked I, Meerson A, Wolf Y, Avni R, Greenberg D, Gilboa-Geffen A, Soreq H (2009) MicroRNA-132 potentiates cholinergic anti-inflammatory signaling by targeting acetylcholinesterase. Immunity 31:965–973

    Article  CAS  PubMed  Google Scholar 

  • Shimazu R, Akashi S, Ogata H, Nagai Y, Fukudome K, Miyake K, Kimoto M (1999) MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. J Exp Med 189:1777–1782

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sklan EH, Podoly E, Soreq H (2006) RACK1 has the nerve to act: structure meets function in the nervous system. Prog Neurobiol 78:117–134

    Article  CAS  PubMed  Google Scholar 

  • Sluzewska A, Rybakowski JK, Laciak M, Mackiewicz A, Sobieska M, Wiktorowicz K (1995) Interleukin-6 serum levels in depressed patients before and after treatment with fluoxetine. Ann N Y Acad Sci 762:474–476

    Article  CAS  PubMed  Google Scholar 

  • Soreq H, Seidman S (2001) Acetylcholinesterase–new roles for an old actor. Nat Rev Neurosci 2:294–302

    Google Scholar 

  • Stebbins EG, Mochly-Rosen D (2001) Binding specificity for RACK1 resides in the V5 region of beta II protein kinase C. J Biol Chem 276:29644–29650

    Article  CAS  PubMed  Google Scholar 

  • Steingard RJ, Yurgelun-Todd DA, Hennen J, Moore JC, Moore CM, Vakili K, Young AD, Katic A, Beardslee WR, Renshaw PF (2000) Increased orbitofrontal cortex levels of choline in depressed adolescents as detected by in vivo proton magnetic resonance spectroscopy. Biol Psychiatry 48:1053–1061

    Article  CAS  PubMed  Google Scholar 

  • Tarsy D, Leopold N, Sax DS (1972) Cholinergic-adrenergic hypothesis of mania and depression. Lancet 2:1153

    Article  CAS  PubMed  Google Scholar 

  • Thornton C, Tang KC, Phamluong K, Luong K, Vagts A, Nikanjam D, Yaka R, Ron D (2004) Spatial and temporal regulation of RACK1 function and N-methyl-D-aspartate receptor activity through WD40 motif-mediated dimerization. J Biol Chem 279:31357–31364

    Article  CAS  PubMed  Google Scholar 

  • Tracey KJ (2002) The inflammatory reflex. Nature 420:853–859

    Article  CAS  PubMed  Google Scholar 

  • Trott O, Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31:455–461

    CAS  PubMed Central  PubMed  Google Scholar 

  • Valledor AF, Xaus J, Comalada M, Soler C, Celada A (2000) Protein kinase C epsilon is required for the induction of mitogen-activated protein kinase phosphatase-1 in lipopolysaccharide-stimulated macrophages. J Immunol 164:29–37

    Article  CAS  PubMed  Google Scholar 

  • Weeber EJ, Atkins CM, Selcher JC, Varga AW, Mirnikjoo B, Paylor R, Leitges M, Sweatt JD (2000) A role for the beta isoform of protein kinase C in fear conditioning. J Neurosci 20:5906–5914

    CAS  PubMed  Google Scholar 

  • Zimmerman G, Shaltiel G, Barbash S, Cohen J, Gasho CJ, Shenhar-Tsarfaty S, Shalev H, Berliner SA, Shelef I, Shoham S et al (2012) Post-traumatic anxiety associates with failure of the innate immune receptor TLR9 to evade the pro-inflammatory NFkappaB pathway. Transl Psychiatry 2:e78

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the Israel Science Foundation’s Legacy-Heritage-Biomedical Science Grant (no. 1876/11) (to HS). NW received a predoctoral fellowship from the Clara Robert Einstein Foundation and AG-G was supported by a FEBS postdoctoral fellowship for work in Bonn. HS and GH are members of the DFG Excellence Cluster ImmunoSensation.

Author information

Authors and Affiliations

  1. Department of Biological Chemistry and The Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem, 91904, Israel

    Nir Waiskopf

  2. Department of Biological Chemistry and The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem, 91904, Israel

    Keren Ofek, Uriya Bekenstein, Estelle R. Bennett & Hermona Soreq

  3. Department of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem, 91904, Israel

    Adi Gilboa-Geffen, Assaf Bahat, Erez Podoly & Oded Livnah

  4. Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital, University of Bonn, Bonn, Germany

    Gunther Hartmann

Authors
  1. Nir Waiskopf
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Keren Ofek
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Adi Gilboa-Geffen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Uriya Bekenstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Assaf Bahat
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Estelle R. Bennett
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Erez Podoly
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Oded Livnah
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Gunther Hartmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hermona Soreq
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hermona Soreq.

Additional information

Nir Waiskopf and Keren Ofek contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Waiskopf, N., Ofek, K., Gilboa-Geffen, A. et al. AChE and RACK1 Promote the Anti-Inflammatory Properties of Fluoxetine. J Mol Neurosci 53, 306–315 (2014). https://doi.org/10.1007/s12031-013-0174-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-013-0174-6

Keywords

Search

Navigation