Fluvoxamine inhibits some inflammatory genes expression in LPS/stimulated human endothelial cells, U937 macrophages, and carrageenan-induced paw edema in rat

Document Type: Original Article


1 Applied Physiology Research Center, Isfahan Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran

2 Department of Pharmacology and Toxicology, Isfahan Pharmaceutical Sciences Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran

3 Applied Physiology Research Center, Isfahan Cardiovascular Research Institute and Department of Physiology, Isfahan University of Medical Sciences, Isfahan, Iran


Objective(s): Fluvoxamine is a well-known selective serotonin reuptake inhibitor (SSRI); Despite its anti-inflammatory effect, little is known about the precise mechanisms involved. In our previous work, we found that IP administration of fluvoxamine produced a noticeable anti-inflammatory effect in carrageenan-induced paw edema in rats. In this study, we aimed to evaluate the effect of fluvoxamine on the expression of some inflammatory genes like intercellular adhesion molecule (ICAM1), vascular cell adhesion molecule (VCAM1), cyclooxygenases2 (COX2), and inducible nitric oxide synthase (iNOS).
Materials and Methods: An in vitro model of LPS stimulated human endothelial cells and U937 macrophages were used. Cells were pretreated with various concentrations of fluvoxamine, from 10-8 M to 10-6 M. For in vivo model, fluvoxamine was administered IP at doses of 25 and 50 mg/kg-1, before injection of carrageenan. At the end of experiment, the expression of mentioned genes were measured by quantitative real time (RT)-PCR in cells and in paw edema in rat.
Results: The expression of ICAM1, VCAM1, COX2, and iNOS was significantly decreased by fluvoxamine in endothelial cells, macrophages, and in rat carrageenan-induced paw edema. Our finding also confirmed that IP injection of fluvoxamine inhibits carrageenan-induced inflammation in rat paw edema.
Conclusion: The results of present study provide further evidence for the anti-inflammatory effect of fluvoxamine. This effect appears to be mediated by down regulation of inflammatory genes. Further studies are needed to evaluate the complex cellular and molecular mechanisms of immunomodulatory effect of fluvoxamine.


1. Leonard BE. The immune system, depression and the action of antidepressants. ProgNeuropsycho-pharmacol Biol Psychiatry. 2001; 25:767–80.

2. Castanon N, Leonard BE, Neveu PJ, Yirmiya R. Effects of antidepressants on cytokine production and actions. Brain Behav Immun. 2002; 16:569–74.

3. Albelda SM, Smith CW, Ward PA. Adhesion molecules and inflammatory injury. FASEB J. 1994; 8:504–12.

4. Sadeghi H, Hajhashemi V, Minaiyan M, Movahedian A, Talebi A. Further studies on anti-inflammatory activity of maprotiline in carrageenan-induced paw edema in rat. Int Immunopharmacol. 2013; 15:505–10.

5. Morham SG, Langenbach R, Loftin CD, Tiano HF, Vouloumanos N, Jennette JC, et al. Prostaglandin synthase 2 gene disruption causes severe renal pathology in the mouse. Cell. 1995; 83:473–82.

6. Barrios-Rodiles M, Chadee K. Novel regulation of cyclooxygenase-2 expression and prostaglandin E2 production by IFN-gamma in human macrophages. J Immunol. 1998; 161:2441–8.

7. Pober JS, Sessa WC. Evolving functions of endothelial cells in inflammation. Nat Rev Immunol. 2007; 7:803–15.

8. Hajhashemi V, Minaiyan M, Eftekhari M. Anti-inflammatory activity of a selection of antidepressant drugs. Iran J Pharm Sci 2008; 4:225–30.

9. Mossman BT, Jean L, Landesman JM. Studies using lectins to determine mineral interactions with cellular membranes. Environ Health Perspect. 1983; 51:23–5.

10. WINTER CA, RISLEY EA, NUSS GW. Carrageenin-induced edema in hind paw of the rat as an assay for antiiflammatory drugs. Proc Soc Exp Biol Med. 1962; 111:544–7.

11. Hajhashemi V, Sadeghi H, Minaiyan M, Movahedian A, Talebi A. Effect of fluvoxamine on carrageenan-induced paw edema in rats evaluation of the action sites. Iran J Pharm Res 2011; 10:611–8.

12. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001; 25:402–8.

13. Muller WA. Leukocyte-endothelial-cell interactions in leukocyte transmigration and the inflammatory response. Trends Immunol. 2003; 24:327–34.

14. Li H, Cybulsky MI, Gimbrone MA, Libby P. Inducible expression of vascular cell adhesion molecule-1 by vascular smooth muscle cells in vitro and within rabbit atheroma. Am J Pathol 1993; 143:1551–9.

15. Lekakis J, Ikonomidis I, Papoutsi Z, Moutsatsou P, Nikolaou M, Parissis J, et al. Selective serotonin re-uptake inhibitors decrease the cytokine-induced endothelial adhesion molecule expression, the endothelial adhesiveness to monocytes and the circulating levels of vascular adhesion molecules. Int J Cardiol 2010; 139:150–8.

16. Barkan T, Gurwitz D, Levy G, Weizman A, Rehavi M. Biochemical and pharmacological characterization of the serotonin transporter in human peripheral blood lymphocytes. Eur Neuropsychopharmacol. 2004; 14:237–43.

17. Fazzino F, Montes C, Urbina M, Carreira I, Lima L. Serotonin transporter is differentially localized in subpopulations of lymphocytes of major depression patients. Effect of fluoxetine on proliferation. J Neuroimmunol. 2008; 196:173–80.

18. Faraj BA, Olkowski ZL, Jackson RT. Expression of a high-affinity serotonin transporter in human lymphocytes. Int J Immunopharmacol. 1994; 16:561–7.

19. Urbina M, Pineda S, Piñango L, Carreira I, Lima L. [3H]Paroxetine binding to human peripheral lymphocyte membranes of patients with major depression before and after treatment with fluoxetine. Int J Immunopharmacol. 1999; 21:631–46.

20. Finocchiaro LM, Arzt ES, Fernández-Castelo S, Criscuolo M, Finkielman S, Nahmod VE. Serotonin and melatonin synthesis in peripheral blood mononuclear cells: stimulation by interferon-gamma as part of an immunomodulatory pathway. J Interferon Res. 1988; 8:705–16.

21. Taler M, Gil-Ad I, Lomnitski L, Korov I, Baharav E, Bar M, et al. Immunomodulatory effect of selective serotonin reuptake inhibitors (SSRIs) on human T lymphocyte function and gene expression. Eur Neuropsychopharmacol 2007; 17:774–80.

22. Diamond M, Kelly JP, Connor TJ. Antidepressants suppress production of the Th1 cytokine interferon-gamma, independent of monoamine transporter blockade. Eur Neuropsychopharmacol 2006; 16:481–90.

23. Hashioka S, Klegeris A, Monji A, Kato T, Sawada M, McGeer PL, et al. Antidepressants inhibit interferon-gamma-induced microglial production of IL-6 and nitric oxide. Exp Neurol 2007; 206:33–42.

24. Tynan RJ, Weidenhofer J, Hinwood M, Cairns MJ, Day TA, Walker FR. A comparative examination of the anti-inflammatory effects of SSRI and SNRI antidepressants on LPS stimulated microglia. Brain Behav Immun. 2012; 26:469–79.

25. Baeuerle PA, Baltimore D. NF-kappa B: ten years after. Cell 1996; 87:13–20.

26. Lee J-K, Choi S-S, Won J-S, Suh H-W. The regulation of inducible nitric oxide synthase gene expression induced by lipopolysaccharide and tumor necrosis factor-alpha in C6 cells: involvement of AP-1 and NFkappaB. Life Sci 2003; 73:595–609.

27. Yamamoto Y, Gaynor RB. IkappaB kinases: key regulators of the NF-kappaB pathway. Trends Biochem Sci. 2004; 29:72–9.

28. Sawa Y, Sugimoto Y, Ueki T, Ishikawa H, Sato A, Nagato T, et al. Effects of TNF-alpha on leukocyte adhesion molecule expressions in cultured human lymphatic endothelium. J Histochem Cytochem. 2007; 55:721–33.

29. Castro-Caldas M, Mendes AF, Carvalho AP, Duarte CB, Lopes MC. Dexamethasone prevents interleukin-1beta-induced nuclear factor-kappaB activation by 

upregulating IkappaB-alpha synthesis, in lymphoblastic cells. Mediators Inflamm. 2003; 12: 37-46.

30. Di Rosa M, Giroud JP, Willoughby DA. Studies on the mediators of the acute inflammatory response induced in rats in different sites by carrageenan and turpentine. J Pathol. 1971; 104:15–29.

31. Gilligan JP, Lovato SJ, Erion MD, Jeng AY. Modulation of carrageenan-induced hind paw edema by substance P. Inflammation 1994; 18:285–92.

32. Gilroy DW, Lawrence T, Perretti M, Rossi AG. Inflammatory resolution: new opportunities for drug discovery. Nat Rev Drug Discov 2004; 3:401–16.

33. Gil-Ad I, Zolokov A, Lomnitski L, Taler M, Bar M, Luria D, et al. Evaluation of the potential anti-cancer activity of the antidepressant sertraline in human colon cancer cell lines and in colorectal cancer-xenografted mice. Int J Oncol 2008; 33:277–86.