Skip to main content
SpringerLink
Log in

Fluoxetine Inhibits Hyperresponsive Lamina Propria Mononuclear Cells and Bone Marrow-Derived Dendritic Cells, and Ameliorates Chronic Colitis in IL-10-Deficient Mice

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Background/Aims

We aimed to study the effect of fluoxetine on chronic colitis and its anti-inflammatory mechanism in interleukin-10-deficient (IL-10−/−) mice.

Methods

IL-10−/− mice were administered with either the vehicle or one of the two dosages of fluoxetine (1 or 5 mg/kg) by oral gavage daily for 2 weeks. Lamina propria mononuclear cells (LPMCs) were isolated from IL-10−/− mice treated with or without fluoxetine, and cytokine expression was measured. Bone marrow-derived dendritic cells (BMDCs) isolated from IL-10−/−, and wild-type mice were pretreated with fluoxetine and then stimulated with lipopolysaccharide. IL-12p40 and tumor necrosis factor (TNF)-α gene expression was determined by real-time PCR. DNA-binding activity of nuclear factor-κB (NF-κB) was evaluated by electrophoretic mobility shift assay.

Results

Fluoxetine significantly reduced intestinal inflammation as assessed by body weight, colon length, and histopathological grading, and it inhibited the level of TNF-α gene expression in IL-10−/− mice. LPMCs were isolated from IL-10−/− mice, and cellular expression of IL-12p40 and interferon-γ was suppressed by fluoxetine treatment. Fluoxetine significantly inhibited IL-12p40 and TNF-α gene expression and protein secretion in BMDCs from IL-10−/− mice. DNA-binding activity of NF-κB was suppressed by fluoxetine pretreatment.

Conclusions

These results indicate that fluoxetine ameliorates intestinal inflammation in IL-10−/− mice and inhibits hyperresponsive LPMCs and BMDCs, which suggests that fluoxetine could be a potential therapeutic agent for inflammatory bowel disease.

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

  1. Baert F, Moortgat L, Van Assche G, et al. Mucosal healing predicts sustained clinical remission in patients with early-stage Crohn’s disease. Gastroenterology. 2010;138:463–468; quiz e410–e461.

  2. Ljung T, Karlen P, Schmidt D, et al. Infliximab in inflammatory bowel disease: clinical outcome in a population based cohort from Stockholm County. Gut. 2004;53:849–853.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Sommi RW, Crismon ML, Bowden CL. Fluoxetine: a serotonin-specific, second-generation antidepressant. Pharmacotherapy. 1987;7:1–15.

    CAS  PubMed  Google Scholar 

  4. Roumestan C, Michel A, Bichon F, et al. Anti-inflammatory properties of desipramine and fluoxetine. Respir Res. 2007;8:35.

    Article  PubMed Central  PubMed  Google Scholar 

  5. Koh SJ, Kim JM, Kim IK, et al. Fluoxetine inhibits NF-kappaB signaling in intestinal epithelial cells and ameliorates experimental colitis and colitis-associated colon cancer in mice. Am J Physiol Gastrointest Liver Physiol.301:G9-19.

  6. Becker C, Wirtz S, Blessing M, et al. Constitutive p40 promoter activation and IL-23 production in the terminal ileum mediated by dendritic cells. J Clin Invest. 2003;112:693–706.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Trinchieri G, Pflanz S, Kastelein RA. The IL-12 family of heterodimeric cytokines: new players in the regulation of T cell responses. Immunity. 2003;19:641–644.

    Article  CAS  PubMed  Google Scholar 

  8. MacDonald TT, Monteleone I, Fantini MC, Monteleone G. Regulation of homeostasis and inflammation in the intestine. Gastroenterology. 2011;140:1768–1775.

    Article  CAS  PubMed  Google Scholar 

  9. Oppmann B, Lesley R, Blom B, et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity. 2000;13:715–725.

    Article  CAS  PubMed  Google Scholar 

  10. Bouma G, Strober W. The immunological and genetic basis of inflammatory bowel disease. Nat Rev Immunol. 2003;3:521–533.

    Article  CAS  PubMed  Google Scholar 

  11. Trinchieri G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol. 2003;3:133–146.

    Article  CAS  PubMed  Google Scholar 

  12. Hoentjen F, Sartor RB, Ozaki M, Jobin C. STAT3 regulates NF-kappaB recruitment to the IL-12p40 promoter in dendritic cells. Blood. 2005;105:689–696.

    Article  CAS  PubMed  Google Scholar 

  13. Karrasch T, Kim JS, Muhlbauer M, Magness ST, Jobin C. Gnotobiotic IL-10−/−;NF-kappa B(EGFP) mice reveal the critical role of TLR/NF-kappa B signaling in commensal bacteria-induced colitis. J Immunol. 2007;178:6522–6532.

    Article  CAS  PubMed  Google Scholar 

  14. Rescigno M, Di Sabatino A. Dendritic cells in intestinal homeostasis and disease. J Clin Invest. 2009;119:2441–2450.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Berg DJ, Zhang J, Weinstock JV, et al. Rapid development of colitis in NSAID-treated IL-10-deficient mice. Gastroenterology. 2002;123:1527–1542.

    Article  CAS  PubMed  Google Scholar 

  16. Weigmann B, Tubbe I, Seidel D, Nicolaev A, Becker C, Neurath MF. Isolation and subsequent analysis of murine lamina propria mononuclear cells from colonic tissue. Nat Protoc. 2007;2:2307–2311.

    Article  CAS  PubMed  Google Scholar 

  17. Lee JY, Kim H, Cha MY, et al. Clostridium difficile toxin A promotes dendritic cell maturation and chemokine CXCL2 expression through p38, IKK, and the NF-kappaB signaling pathway. J Mol Med. 2009;87:169–180.

    Article  CAS  PubMed  Google Scholar 

  18. Cheon JH, Kim JS, Kim JM, et al. Plant sterol guggulsterone inhibits nuclear factor-kappaB signaling in intestinal epithelial cells by blocking IkappaB kinase and ameliorates acute murine colitis. Inflamm Bowel Dis. 2006;12:1152–1161.

    Article  PubMed  Google Scholar 

  19. Coombes JL, Siddiqui KR, Arancibia-Carcamo CV, et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J Exp Med. 2007;204:1757–1764.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Abdel-Salam OM, Baiuomy AR, Arbid MS. Studies on the anti-inflammatory effect of fluoxetine in the rat. Pharmacol Res. 2004;49:119–131.

    Article  CAS  PubMed  Google Scholar 

  21. Davidson NJ, Hudak SA, Lesley RE, Menon S, Leach MW, Rennick DM. IL-12, but not IFN-gamma, plays a major role in sustaining the chronic phase of colitis in IL-10-deficient mice. J Immunol. 1998;161:3143–3149.

    CAS  PubMed  Google Scholar 

  22. Trinchieri G. Interleukin-12: a cytokine produced by antigen-presenting cells with immunoregulatory functions in the generation of T-helper cells type 1 and cytotoxic lymphocytes. Blood. 1994;84:4008–4027.

    CAS  PubMed  Google Scholar 

  23. Magram J, Connaughton SE, Warrier RR, et al. IL-12-deficient mice are defective in IFN gamma production and type 1 cytokine responses. Immunity. 1996;4:471–481.

    Article  CAS  PubMed  Google Scholar 

  24. Sanjabi S, Hoffmann A, Liou HC, Baltimore D, Smale ST. Selective requirement for c-Rel during IL-12 P40 gene induction in macrophages. Proc Natl Acad Sci USA. 2000;97:12705–12710.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Murphy TL, Cleveland MG, Kulesza P, Magram J, Murphy KM. Regulation of interleukin 12 p40 expression through an NF-kappa B half-site. Mol Cell Biol. 1995;15:5258–5267.

    CAS  PubMed Central  PubMed  Google Scholar 

  26. Plevy SE, Gemberling JH, Hsu S, Dorner AJ, Smale ST. Multiple control elements mediate activation of the murine and human interleukin 12 p40 promoters: evidence of functional synergy between C/EBP and Rel proteins. Mol Cell Biol. 1997;17:4572–4588.

    CAS  PubMed Central  PubMed  Google Scholar 

  27. Jobin C, Sartor RB. The I kappa B/NF-kappa B system: a key determinant of mucosalinflammation and protection. Am J Physiol Cell Physiol. 2000;278:C451–C462.

    CAS  PubMed  Google Scholar 

  28. Ardite E, Panes J, Miranda M, et al. Effects of steroid treatment on activation of nuclear factor kappaB in patients with inflammatory bowel disease. Br J Pharmacol. 1998;124:431–433.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Egan LJ, Mays DC, Huntoon CJ, et al. Inhibition of interleukin-1-stimulated NF-kappaB RelA/p65 phosphorylation by mesalamine is accompanied by decreased transcriptional activity. J Biol Chem. 1999;274:26448–26453.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by Research Settlement Fund for the new faculty of SNU and Grant No. 04-2011-0760 from the SNUH Research Fund.

Conflict of interest

None of the authors had conflicts of interest that potentially influence the described research.

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Seoul National University Boramae Hospital, Seoul National University College of Medicine, 5 Gil 20, Boramae-Road, Dongjak-Gu, Seoul, 156–707, South Korea

    Seong-Joon Koh, Ji Won Kim, Byeong Gwan Kim & Kook Lae Lee

  2. Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 28 Yongon-Dong, Chongno-Gu, Seoul, 110–744, South Korea

    Jong Pil Im & Joo Sung Kim

Authors
  1. Seong-Joon Koh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ji Won Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Byeong Gwan Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kook Lae Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jong Pil Im
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Joo Sung Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joo Sung Kim.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Koh, SJ., Kim, J.W., Kim, B.G. et al. Fluoxetine Inhibits Hyperresponsive Lamina Propria Mononuclear Cells and Bone Marrow-Derived Dendritic Cells, and Ameliorates Chronic Colitis in IL-10-Deficient Mice. Dig Dis Sci 60, 101–108 (2015). https://doi.org/10.1007/s10620-014-3326-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-014-3326-9

Keywords

Search

Navigation