Niacin inhibits carrageenan-induced neutrophil migration in mice

  • Raphael Gomes Ferreira
  • Tamires Cardoso Matsui
  • Lindisley Ferreira Gomides
  • Adriana Martins Godin
  • Gustavo Batista Menezes
  • Márcio de Matos Coelho
  • André KleinEmail author
Original Article


Several emerging lines of evidence support an anti-inflammatory role for nicotinic acid (niacin); however, its role in the regulation of leukocyte migration in response to inflammatory stimuli has not been elucidated until now. Herein, we have examined the effect of nicotinic acid on neutrophil recruitment in experimentally induced inflammation. We demonstrated that nicotinic acid treatment inhibited interleukin (IL)-8-induced, leukotriene (LT)B4-induced, and carrageenan-induced neutrophil migration into the pleural cavity of BALB/c mice and reduced neutrophil rolling and adherence in a mouse cremaster muscle preparation. Surprisingly, nicotinic acid treatment increased the level of the neutrophil chemoattractant KC in response to carrageenan. These results suggest that nicotinic acid plays an important role in the regulation of inflammation due to its ability to inhibit the actions of the neutrophil chemoattractants IL-8 and LTB4. Further inhibition of chemoattractants leads to impairment of leukocyte rolling and adherence to the vascular endothelium in the microcirculation of inflamed tissues.


Inflammatory response Neutrophil recruitment Niacin Nicotinic acid Pleurisy 



This work was supported by Fundação de Amparo à Pesquisa de Minas Gerais (FAPEMIG) and Conselho Nacional de Pesquisa e Desenvolvimento (CNPq), Brazil. The authors are grateful to W.G. Pimenta for his excellent technical assistance. R.G.F., A.M.G., and L.F.G. are graduate student fellows from CAPES, Brazil.

Conflict of interest

The authors declare they have no conflict of interest.

Supplementary material


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  1. Baggiolini M, Clark-Lewis I (1992) Interleukin-8, a chemotactic and inflammatory cytokine. FEBS Lett 307:97–101PubMedCrossRefGoogle Scholar
  2. Bhattacharyya S, Gill R, Chen ML, Zhang F, Linhardt RJ, Dudeja PK et al (2008) Toll-like receptor 4 mediates induction of the Bcl10-NFkappaB-interleukin-8 inflammatory pathway by carrageenan in human intestinal epithelial cells. J Biol Chem 283:10550–10558PubMedCrossRefGoogle Scholar
  3. Brentano F, Schorr O, Ospelt C, Stanczyk J, Gay RE, Gay S et al (2007) Pre-B cell colony-enhancing factor/visfatin, a new marker of inflammation in rheumatoid arthritis with proinflammatory and matrix-degrading activities. Arthritis Rheum 56:2829–2839PubMedCrossRefGoogle Scholar
  4. Bruzzone S, Fruscione F, Morando S, Ferrando T, Poggi A, Garuti A et al (2009) Catastrophic NAD+ depletion in activated T lymphocytes through Nampt inhibition reduces demyelination and disability in EAE. PLoS One 4(11):e7897PubMedCrossRefGoogle Scholar
  5. Busso N, Karababa M, Nobile M, Rolaz A, Van Gool F, Galli M, Leo O, So A, De Smedt T (2008) Pharmacological inhibition of nicotinamide phosphoribosyltransferase/visfatin enzymatic activity identifies a new inflammatory pathway linked to NAD. PLoS One 3(5):e2267PubMedCrossRefGoogle Scholar
  6. Byrum RS, Goulet JL, Snouwaert JN, Griffiths RJ, Koller BH (1999) Determination of the contribution of cysteinyl leukotrienes and leukotriene B4 in acute inflammatory responses using 5-lipoxygenase- and leukotriene A4 hydrolase-deficient mice. J Immunol 163:6810–6819PubMedGoogle Scholar
  7. Faurschou M, Borregaard N (2003) Neutrophil granules and secretory vesicles in inflammation. Microbes Infect 5:1317–1327PubMedCrossRefGoogle Scholar
  8. Ganji SH, Qin S, Zhang L, Kamanna VS, Kashyap ML (2009) Niacin inhibits vascular oxidative stress, redox-sensitive genes, and monocyte adhesion to human aortic endothelial cells. Atherosclerosis 202:68–75PubMedCrossRefGoogle Scholar
  9. Godin AM, Ferreira WC, Rocha LT, Ferreira RG, Paiva AL, Merlo LA, Nascimento EB Jr, Bastos LF, Coelho MM (2012) Nicotinic acid induces antinociceptive and anti-inflammatory effects in different experimental models. Pharmacol Biochem Behav 101:493–498PubMedCrossRefGoogle Scholar
  10. Gurujeyalakshmi G, Wang Y, Giri SN (2000) Taurine and niacin block lung injury and fibrosis by down-regulating bleomycin-induced activation of transcription nuclear factor-kappaB in mice. J Pharmacol Exp Ther 293:82–90PubMedGoogle Scholar
  11. Hageman GJ, Stierum RH (2001) Niacin, poly(ADP-ribose) polymerase-1 and genomic stability. Mutat Res 475:45–56PubMedCrossRefGoogle Scholar
  12. Hickey MJ, Sharkey KA, Sihota EG, Reinhardt PH, Macmicking JD, Nathan C, Kubes P (1997) Inducible nitric oxide synthase-deficient mice have enhanced leukocyte–endothelium interactions in endotoxemia. FASEB J 11:955–964PubMedGoogle Scholar
  13. Kirkland JB (2009) Niacin status, NAD distribution and ADP-ribose metabolism. Curr Pharm Des 15:3–11PubMedCrossRefGoogle Scholar
  14. Klein A, Talvani A, Silva PM, Martins MA, Wells TN, Proudfoot A, Luckacs NW, Teixeira MM (2001) Stem cell factor-induced leukotriene B4 production cooperates with eotaxin to mediate the recruitment of eosinophils during allergic pleurisy in mice. J Immunol 167:524–531PubMedGoogle Scholar
  15. Kobayashi Y (2008) The role of chemokines in neutrophil biology. Front Biosci 13:2400–2407PubMedCrossRefGoogle Scholar
  16. Kobayashi SD, DeLeo FR (2009) Role of neutrophils in innate immunity: a systems biology-level approach. Wiley Interdiscip Rev Syst Biol Med 1:309–333PubMedCrossRefGoogle Scholar
  17. Kostylina G, Simon D, Fey MF, Yousefi S, Simon HU (2008) Neutrophil apoptosis mediated by nicotinic acid receptors (GPR109A). Cell Death Differ 15:134–142PubMedCrossRefGoogle Scholar
  18. Kubes P, Suzuki M, Granger DN (1991) Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci U S A 88:4651–4655PubMedCrossRefGoogle Scholar
  19. Kunkel EJ, Jung U, Bullard DC, Norman KE, Wolitzky BA, Vestweber D, Beaudet AL, Ley K (1996) Absence of trauma-induced leukocyte rolling in mice deficient in both P-selectin and intercellular adhesion molecule 1. J Exp Med 183:57–65PubMedCrossRefGoogle Scholar
  20. Kwon WY, Suh GJ, Kim KS, Kwak YH (2011) Niacin attenuates lung inflammation and improves survival during sepsis by downregulating the nuclear factor-kappaB pathway. Crit Care Med 39:328–334PubMedCrossRefGoogle Scholar
  21. Luk T, Malam Z, Marshall JC (2008) Pre-B cell colony-enhancing factor (PBEF)/visfatin: a novel mediator of innate immunity. J Leukoc Biol 83:804–816PubMedCrossRefGoogle Scholar
  22. Mathieu J, Tissot M, Nolibe D, Florentin I, Kergonou JF, Giroud JP (1990) Local and systemic effects of an acute inflammation on eicosanoid generation capacity of polymorphonuclear cells and macrophages. Int J Exp Pathol 71:603–616PubMedGoogle Scholar
  23. Menezes GB, Rezende RM, Pereira-Silva PE, Klein A, Cara DC, Francischi JN (2008) Differential involvement of cyclooxygenase isoforms in neutrophil migration in vivo and in vitro. Eur J Pharmacol 598:118–122PubMedCrossRefGoogle Scholar
  24. Nagai A, Yasui S, Ozawa Y, Uno H, Konno K (1994) Niacin attenuates acute lung injury induced by lipopolysaccharide in the hamster. Eur Respir J 7:1125–1130PubMedGoogle Scholar
  25. Peng Q, Li K, Sacks SH, Zhou W (2009) The role of anaphylatoxins C3a and C5a in regulating innate and adaptive immune responses. Inflamm Allergy Drug Targets 8:236–246PubMedCrossRefGoogle Scholar
  26. Ramos CD, Heluy-Neto NE, Ribeiro RA, Ferreira SH, Cunha FQ (2003) Neutrophil migration induced by IL-8-activated mast cells is mediated by CINC-1. Cytokine 21:214–223PubMedCrossRefGoogle Scholar
  27. Raychaudhuri A, Chertock H, Chovan J, Jones LS, Kimble EF, Kowalski TJ, Peppard J, White DH, Satoh Y, Roland D (1997) Inhibition of LTB4 biosynthesis in situ by CGS 23885, a potent 5-lipoxygenase inhibitor, correlates with its pleural fluid concentrations in an experimentally induced rat pleurisy model. Naunyn Schmiedebergs Arch Pharmacol 355:470–474PubMedCrossRefGoogle Scholar
  28. Rongvaux A, Andris F, Van Gool F, Leo O (2003) Reconstructing eukaryotic NAD metabolism. Bioessays 25:683–690PubMedCrossRefGoogle Scholar
  29. Samuelsson B (1983) Leukotrienes: mediators of immediate hypersensitivity reactions and inflammation. Science 220:568–575PubMedCrossRefGoogle Scholar
  30. Seo SM, McIntire LV, Smith CW (2001) Effects of IL-8, Gro-alpha, and LTB(4) on the adhesive kinetics of LFA-1 and Mac-1 on human neutrophils. Am J Physiol Cell Physiol 281(C1):568–578Google Scholar
  31. Soga T, Kamohara M, Takasaki J, Matsumoto S, Saito T, Ohishi T, Hiyama H, Matsuo A, Matsushime H, Furuichi K (2003) Molecular identification of nicotinic acid receptor. Biochem Biophys Res Commun 303:364–369PubMedCrossRefGoogle Scholar
  32. Szabo C, Lim LH, Cuzzocrea S, Getting SJ, Zingarelli B, Flower RJ et al (1997) Inhibition of poly (ADP-ribose) synthetase attenuates neutrophil recruitment and exerts antiinflammatory effects. J Exp Med 186:1041–1049PubMedCrossRefGoogle Scholar
  33. Tavintharan S, Lim SC, Sum CF (2009) Effects of niacin on cell adhesion and early atherogenesis: biochemical and functional findings in endothelial cells. Basic Clin Pharmacol Toxicol 104:206–210PubMedCrossRefGoogle Scholar
  34. Tunaru S, Kero J, Schaub A, Wufka C, Blaukat A, Pfeffer K, Offermanns S (2003) PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect. Nat Med 9:352–355PubMedCrossRefGoogle Scholar
  35. Van Gool F, Galli M, Gueydan C, Kruys V, Prevot PP, Bedalov A, Mostoslavsky R, Alt FW, De Smedt T, Leo O (2009) Intracellular NAD levels regulate tumor necrosis factor protein synthesis in a sirtuin-dependent manner. Nat Med 15:206–210PubMedCrossRefGoogle Scholar
  36. Vicaut E, Stucker O (1990) An intact cremaster muscle preparation for studying the microcirculation by in vivo microscopy. Microvasc Res 39:120–122PubMedCrossRefGoogle Scholar
  37. Wang QJ, Giri SN, Hyde DM, Nakashima JM, Javadi I (1990) Niacin attenuates bleomycin-induced lung fibrosis in the hamster. J Biochem Toxicol 5:13–22PubMedCrossRefGoogle Scholar
  38. Weiss SJ (1989) Tissue destruction by neutrophils. N Engl J Med 320:365–376PubMedCrossRefGoogle Scholar
  39. Wise A, Foord SM, Fraser NJ, Barnes AA, Elshourbagy N, Eilert M, Ignar DM, Murdock PR, Steplewski K, Green A, Brown AJ, Dowell SJ, Szekeres PG, Hassall DG, Marshall FH, Wilson S, Pike NB (2003) Molecular identification of high and low affinity receptors for nicotinic acid. J Biol Chem 278:9869–9874PubMedCrossRefGoogle Scholar
  40. Yang XD, Corvalan JR, Wang P, Roy CM, Davis CG (1999) Fully human anti-interleukin-8 monoclonal antibodies: potential therapeutics for the treatment of inflammatory disease states. J Leukoc Biol 66:401–410PubMedGoogle Scholar
  41. Yokomizo T, Izumi T, Chang K, Takuwa Y, Shimizu TA (1997) G-protein-coupled receptor for leukotriene B4 that mediates chemotaxis. Nature 387:620–624PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Raphael Gomes Ferreira
    • 1
  • Tamires Cardoso Matsui
    • 1
  • Lindisley Ferreira Gomides
    • 1
  • Adriana Martins Godin
    • 2
  • Gustavo Batista Menezes
    • 3
  • Márcio de Matos Coelho
    • 2
  • André Klein
    • 1
    • 4
    Email author
  1. 1.Laboratory of Inflammation and Pain, Institute of Biological SciencesUFMGBelo HorizonteBrazil
  2. 2.Laboratory of Pharmacology, Faculty of Pharmaceutical SciencesUFMGBelo HorizonteBrazil
  3. 3.Department of Morphology, Institute of Biological SciencesUFMGBelo HorizonteBrazil
  4. 4.Department of Pharmacology, Institute of Biological SciencesFederal University of Minas GeraisBelo HorizonteBrazil

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