Skip to main content

Advertisement

SpringerLink
Log in

Naringin Attenuates the Development of Carrageenan-Induced Acute Lung Inflammation Through Inhibition of NF-κb, STAT3 and Pro-Inflammatory Mediators and Enhancement of IκBα and Anti-Inflammatory Cytokines

  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Naringin has been reported to possess diverse pharmacological properties, including anti-arthritic and anti-inflammatory activities. The aim of the present study was to determine the potential anti-inflammatory effect of naringin in a mouse model of carrageenan-induced pleurisy. A single dose of naringin (40 and 80 mg/kg) was administered per oral (p.o.) 1 h before carrageenan (Cg) administration. Pro- and anti-inflammatory cytokines were analysed in pleural fluid. We also assessed the effects of naringin on the expression levels of iNOS, inducible cyclooxygenase isoform (COX-2), ICAM-1, MIP-2, PGE2, STAT3, TGF-β1, nuclear factor kappa B (NF-κB) and inhibitor of kappa B (IκBα) in lung tissue. The histological examinations revealed anti-inflammatory effect of naringin while Cg group deteriorated. Naringin downregulated Th1 and upregulated Th2 cytokines. Western blot analyses revealed increased protein expression of NF-κB, STAT3 and COX-2 and decreased IκBα in response to Cg treatment, which were reversed by the treatment with naringin. In the Cg group, mRNA expression levels of pro-inflammatory mediators upregulated and anti-inflammatory mediators downregulated. Naringin reversed these actions.

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
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Glasser, G., E.U. Graefe, F. Struck, M. Veit, and R. Gebhardt. 2002. Comparison of antioxidative capacities and inhibitory effects on cholesterol biosynthesis of quercetin and potential metabolites. Phytomedicine 9(1): 33–40.

    Article  CAS  PubMed  Google Scholar 

  2. Maksimovic, Z., D. Malencić, and N. Kovacevic. 2005. Polyphenol contents and antioxidant activity of Maydis stigma extracts. Bioresource Technology 96(8): 873–877.

    Article  CAS  PubMed  Google Scholar 

  3. Sekar, T., and K. Francis. 1999. A preliminary investigation of some Maruthamalai forest plants for phytochemical compounds. Bioresource Technology 70(3): 303–304.

    Article  CAS  Google Scholar 

  4. Rajadurai, M., P. Stanely, and M. Prince. 2009. Naringin ameliorates mitochondrial lipid peroxides, antioxidants and lipids in isoproterenol-induced myocardial infarction in Wistar rats. Phytotherapy Research 23: 358–362.

    Article  CAS  PubMed  Google Scholar 

  5. Kim, H.J., J.Y. Song, H.J. Park, H.K. Park, D.H. Yun, and J.H. Chung. 2009. Naringin protects against rotenone-induced apoptosis in human neuroblastoma SH-SY5Y cells. Korean journal of physiology and pharmacology 13: 281–285.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Jagetia, G.C., and T.K. Reddy. 2005. Modulation of radiation induced alteration in the antioxidant status of mice by naringin. Life Sciences 77: 780–794.

    Article  CAS  PubMed  Google Scholar 

  7. Ribeiro, M., A. Barateiro, H. Vila-Real, A. Fernandes, and D. Brites. 2009. Anti-inflammatory effect of naringin and naringenin on TNF-α secretion in cultured cortical astrocytes after stimulation with LPS. New Biotechnology 25: S10–S11.

    Article  Google Scholar 

  8. Ahmad, S.F., K.M. Zoheir, H.E. Abdel-Hamied, A.E. Ashour, S.A. Bakheet, S.M. Attia, and A.R. Abd-Allah. 2014. Amelioration of autoimmune arthritis by naringin through modulation of T regulatory cells and Th1/Th2 cytokines. Cell Immunology 287(2): 112–120.

    Article  CAS  Google Scholar 

  9. Lentsch, A.B.., and P.A. Ward. 2001. Regulation of experimental lung inflammation. Respiration Physiology 128: 17–21.

    Article  CAS  PubMed  Google Scholar 

  10. Nantel, F., D. Denis, R. Gordon, A. Northey, M. Cirino, K.M. Metters, and C.C. Chan. 1999. Distribution and regulation of cyclooxygenase-2 in carrageenan-induced inflammation. British Journal of Pharmacology 4: 853–859.

    Article  Google Scholar 

  11. Cawthorn, W.P., and J.K. Sethi. 2008. TNF-alpha and adipocyte biology. FEBS Letters 9 582(1): 117–131.

    Article  CAS  Google Scholar 

  12. Bhatia, M., F.L. Wong, Y. Cao, H.Y. Lau, J. Huang, and P. Puneet. 2005. Pathophysiology of acute pancreatitis. Pancreatology 5: 132–144.

    Article  PubMed  Google Scholar 

  13. Korn, T., E. Betteli, M. Oukka, and V.K. Kuchroo. 2009. IL-17 and Th17 cells. Annual Review of Immunology 27: 485–517.

    Article  CAS  PubMed  Google Scholar 

  14. Shin, D.I., U. Banning, and Y.M. Kim. 1999. Interleukin 10 inhibits TNF-alpha production in human monocytes independently of interleukin 12 and interleukin 1 beta. Immunological Investigations 28: 165–175.

    Article  CAS  PubMed  Google Scholar 

  15. Harris, R., J.A. McKanna, Y. Akai, H.R. Jacobson, R.N. Dubois, and M.D. Breyer. 1994. Cyclooxygenase-2 478 is associated with the macula densa of rat kidney and increases with salt restriction. Journal of Clinical Investigation 94: 2504–2510.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Bharti, A.C., and B.B. Aggarwal. 2002. Nuclear factor-kappa B and cancer: its role in prevention 476 and therapy. Biochemical Pharmacology 64: 883–888.

    Article  CAS  PubMed  Google Scholar 

  17. Hinz, M., S.C. Arslan, and C. Scheidereit. 2012. It takes two to tango: IκBs, the multifunctional partners of NFkB. Immunological Reviews 246: 59–76.

    Article  PubMed  Google Scholar 

  18. Ghosh, S., and M.S. Hayden. 2009. New regulators of NFκB in inflammation. Nature Immunology 10: 158–166.

    Article  PubMed Central  PubMed  Google Scholar 

  19. Zhong, Z., Z. Wen, and J.E. Darnell Jr. 1994. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science 264: 95–98.

    Article  CAS  PubMed  Google Scholar 

  20. Ahmad, S.F., K.M. Zoheir, H.E. Abdel-Hamied, S.M. Attia, S.A. Bakheet, A.E. Ashour, and A.R. Abd-Allah. 2014. Grape seed proanthocyanidin extract protects against Carrageenan-induced lung inflammation in mice through reduction of Pro-inflammatory markers and Chemokine expressions. Inflammation 37(2): 500–511.

    Article  CAS  PubMed  Google Scholar 

  21. Impellizzeri, D., E. Esposito, E. Mazzon, I. Paterniti, P.R. Di, P. Bramanti, and S. Cuzzocrea. 2011. Effect of apocynin, a NADPH oxidase inhibitor, on acute lung inflammation. Biochemical Pharmacology 81(5): 636–648.

    Article  CAS  PubMed  Google Scholar 

  22. Ahmad, S.F., Zoheir, K.M., Abdel-Hamied, H.E., Alrashidi, I., Attia, S.M., Bakheet, S.A., Ashour, A.E., Abd-Allah, A.R. 2014. The role of a histamine 4 receptor as an anti-inflammatory target in carrageenan-induced pleurisy in mice. Immunology. 142(3):374–83. doi: 10.1111/imm.12257. [Epub ahead of print].

  23. Barakat, A., K. Szick-Miranda, I.F. Chang, R. Guyot, G. Blanc, R. Cooke, M. Delseny, and J. Bailey-Serres. 2001. The organization of cytoplasmic ribosomal protein genes in the Arabidopsis genome. Plant Physiology 127(2): 398–415.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Korashy, H.M., and A.O. El-Kadi. 2004. Differential effects of mercury, lead and copper on the constitutive and inducible expression of aryl hydrocarbon receptor (AHR)-regulated genes in cultured hepatoma Hepa 1c1c7 cells. Toxicology 1 201(1–3): 153–172.

    Article  CAS  Google Scholar 

  25. Sambrook, J., Fritsch, E.F., Maniatatis, T. Ford, N. 1989. (ed), Molecular cloning. A laboratory manual, Cold Spring Harbour Laboratory Press, Plainview, NY.

  26. Ahmad, S.F., K.M. Zoheir, H.E. Abdel-Hamied, A.E. Ashour, S.A. Bakheet, S.M. Attia, and A.R. Abd-Allah. 2013. Grape seed proanthocyanidin extract has potent anti-arthritic effects on collagen-induced arthritis by modifying the T cell balance. International Immunopharmacology 17(1): 79–87.

    Article  CAS  PubMed  Google Scholar 

  27. Ahmad, S.F., S.M. Attia, K.M. Zoheir, A.E. Ashour, and S.A. Bakheet. 2014. Attenuation of the progression of adjuvant-induced arthritis by 3-aminobenzamide treatment. International Immunopharmacology 19(1): 52–59.

    Article  CAS  PubMed  Google Scholar 

  28. Kanno, S., A. Shouji, A. Tomizawa, T. Hiura, Y. Osanai, M. Ujibe, Y. Obara, N. Nakahata, and M. Ishikawa. 2006. Inhibitory effect of naringin on lipopolysaccharide-induced endotoxin shock in mice and nitric oxide production in RAW264.7 macrophages. Life Sciences 78: 673–681.

    Article  CAS  PubMed  Google Scholar 

  29. Lee, E.Y., C.K. Lee, K.U. Lee, J.Y. Park, K.J. Cho, Y.S. Cho, et al. 2007. Alpha-lipoic acid suppresses the development of collagen-induced arthritis and protects against bone destruction in mice. Rheumatology International 27: 225–233.

    Article  CAS  PubMed  Google Scholar 

  30. Zhao, L., J.Y. Tao, S.L. Zhang, R. Pang, F. Jin, J.H. Dong, and Y.J. Guo. 2007. Inner anti-inflammatory mechanisms of petroleum ether extract from Melilotus suaveolens Ledeb. Inflammation 30: 213–223.

    Article  PubMed  Google Scholar 

  31. Alonzi, T., E. Fattori, M. Cappelletti, G. Ciliberto, and V. Poli. 1998. Impaired stat3 activation following localized inflammatory stimulus in IL-6 deficient mice. Cytokine 10: 13–18.

    Article  CAS  PubMed  Google Scholar 

  32. Borish, L.C., and J.W. Steinke. 2003. Cytokines and chemokines. Journal of Allergy and Clinical Immunology 111: 460–475.

    Article  Google Scholar 

  33. Menegazzi, M., R. Di Paola, E. Mazzon, T. Genovese, and C. Crisafulli. 2008. Glycyrrhizin attenuates the development of carrageenan-induced lung injury in mice. Pharmacological Research 58: 22–31.

    Article  CAS  PubMed  Google Scholar 

  34. Calcagni, E., and I. Elenkov. 2006. Stress system activity, innate and T helper cytokines, and susceptibility to immune-related diseases. Annals of the New York Academy of Sciences 1069: 62–76.

    Article  CAS  PubMed  Google Scholar 

  35. Stow, J.L., P.C. Low, C. Offenhauser, and D. Sangermani. 2009. Cytokine secretion in macrophages and other cells: pathways and mediators. Immunobiology 214: 601–612.

    Article  CAS  PubMed  Google Scholar 

  36. Hurst, S.D., T. Muchamuel, D.M. Gorman, J.M. Gilbert, T. Clifford, S. Kwan, S. Menon, B. Seymour, C. Jackson, T.T. Kung, J.K. Brieland, S.M. Zurawski, R.W. Chapman, G. Zurawski, and R.L. Coffman. 2002. New IL-17 family members promote Th1 or Th2 responses in the lung: in vivo function of the novel cytokine IL-25. The Journal of Immunology 169: 443–453.

    Article  CAS  PubMed  Google Scholar 

  37. Li, L., L. Huang, A.L. Vergis, H. Ye, A. Bajwa, V. Narayan, R.M. Strieter, D.L. Rosin, and M.D. Okusa. 2010. IL-17 produced by neutrophils regulates IFN-gamma-mediated neutrophil migration in mouse kidney ischemia-reperfusion injury. Journal of Clinical Investigation 120: 331–342.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Oberholzer, A., C. Oberholzer, and L.L. Moldawer. 2002. Interleukin-10: a complex role in the pathogenesis of sepsis syndromes and its potential as an anti-inflammatory drug. Critical Care Medicine 30(1 Suppl): S58–S63.

    Article  CAS  Google Scholar 

  39. Miossec, P. 1993. Anti-inflammatory properties of interleukin-4. Revue du Rhumatisme 60(2): 119–124.

    CAS  PubMed  Google Scholar 

  40. Karin, M., Ben-Neriah, Y. 2000. Phosphorylation meets ubiquitination: the control of NF-κB activity. Annual Review of Immunology 18:621–663.

  41. Park, K.I., Kang, S.R., Park, H.S., Lee, do. H., Nagappan, A., Kim, J.A., Shin, S.C., Kim, E.H., Lee, W.S., Chung, H.J., An, S.J., Kim, G.S. 2012. Regulation of proinflammatory mediators via NF-κB and p38 MAPK-dependent mechanisms in RAW264.7 macrophages by polyphenol components isolated from Korea Lonicera japonica THUNB. Evidence-Based Complementary and Alternative Medicine 2012:828521.

  42. Ghosh, S., M.J. May, and E.B. Kopp. 1998. NF-κB and rel proteins: evolutionarily conserved mediators of immune responses. Annual Review of Immunology 16: 225–260.

    Article  CAS  PubMed  Google Scholar 

  43. Korhonen, R., A. Lahti, H. Kankaanranta, and E. Moilanen. 2005. Nitric oxide production and signaling in inflammation. Current Drug Targets - Inflammation & Allergy 4: 471–179.

    Article  CAS  Google Scholar 

  44. Cuzzocrea, S., B. Zingarelli, P. Hake, A.L. Salzman, and C. Szab’o. 1998. Anti-inflammatory effects of mercaptoethylguanidine, a combined inhibitor of nitric oxide synthase and peroxynitrite scavenger, in carrageenan-induced models of inflammation. Free Radical Biology and Medicine 24: 450–459.

    Article  CAS  PubMed  Google Scholar 

  45. Chun, K.S., H.H. Cha, J.W. Shin, H.K. Na, K.K. Park, W.Y. Chung, and Y.J. Surh. 2004. Nitiric oxide induces expression of cyclooxygenase-2 inmouse skin through activation of NF-κB. Carcinogenesis 25: 445–454.

    Article  CAS  PubMed  Google Scholar 

  46. Zuckerman, L.A., L. Pullen, and J. Miller. 1998. Functional consequences of costimulation by ICAM-1 on IL-2 gene expression and T cell activation. The Journal of Immunology 160: 3259–3268.

    CAS  PubMed  Google Scholar 

  47. Stanciu, L.A., and R. Djukanovic. 1998. The role of ICAM-1 on T-cells in the pathogenesis of asthma. European Respiratory Journal 11: 949–957.

    Article  CAS  PubMed  Google Scholar 

  48. Matze, S.P., T. Baumann, N.W. Lukacs, M. Rollinghoff, and H.U. Beuscher. 2001. Constitutive expression of macrophage inflammatory protein 2 (MIP-2) mRNA in bone marrow gives rise to peripheral neutrophils with preformed MIP-2 protein. The Journal of Immunology 167: 4635–4643.

    Article  Google Scholar 

  49. Baggiolii, M., B. Dewald, and B. Moser. 1999. Chemokines. In Basic principle and clinical correlates, 3rd ed, ed. J.I. Gallin and R. Snyderman, 419–431. Philadelphia: Lippincott Williams and Wilkins.

    Google Scholar 

  50. Legler, D.F., M. Bruckne, A.E. Uetz-von, and P. Krause. 2010. Prostaglandin E2 at new glance: novel insights in functional diversity offer therapeutic chances. The International Journal of Biochemistry & Cell Biology 42: 198–201.

    Article  CAS  Google Scholar 

  51. Funk, C.D. 2001. Prostaglandins and leukotrienes: advances in eicosanoid biology. Science 294: 1871–1875.

    Article  CAS  PubMed  Google Scholar 

  52. Gao, H., R.F. Guo, C.L. Speyer, J. Reuben, T.A. Neff, and L.M. Hoesel. 2004. Stat3 activation in acute lung injury. The Journal of Immunology 172: 7703–7712.

    Article  CAS  PubMed  Google Scholar 

  53. Kelley, J. 1993. Transforming growth factor-beta. In Cytokines of the lung, ed. J. Kelley, 101–137. New York: Marcel Dekker.

    Google Scholar 

  54. Stapelberg, M., N. Gellert, and E. Swettenham. 2005. Alpha-tocopheryl succinate inhibits malignant mesothelioma by disrupting the fibroblast growth factor autocrine loop: mechanism and the role of oxidative stress. The Journal of Biological Chemistry 280: 25369–25376.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors extend their appreciation to the Deanship of Scientific Research at King Saud University for funding the work through the research group project no. RGP-VPP-120.

Conflict of Interest

The authors declare that there is no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia

    Sheikh Fayaz Ahmad, Sabry M. Attia, Saleh A. Bakheet, Khairy M. A. Zoheir, Mushtaq Ahmad Ansari, Hesham M. Korashy, Abdelkader E. Ashour & Adel R. A. Abd-Allah

  2. Department of Pharmacology and Toxicology, College of Pharmacy, Al-Azhar University, Cairo, Egypt

    Sabry M. Attia & Adel R. A. Abd-Allah

  3. Department of Cell Biology, National Research Centre, Cairo, Egypt

    Khairy M. A. Zoheir

  4. Department of Pathology, Faculty of Medicine (Girls), Al-Azhar University, Cairo, Egypt

    Hala E. Abdel-Hamied

Authors
  1. Sheikh Fayaz Ahmad
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sabry M. Attia
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Saleh A. Bakheet
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Khairy M. A. Zoheir
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mushtaq Ahmad Ansari
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hesham M. Korashy
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hala E. Abdel-Hamied
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Abdelkader E. Ashour
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Adel R. A. Abd-Allah
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sheikh Fayaz Ahmad.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ahmad, S.F., Attia, S.M., Bakheet, S.A. et al. Naringin Attenuates the Development of Carrageenan-Induced Acute Lung Inflammation Through Inhibition of NF-κb, STAT3 and Pro-Inflammatory Mediators and Enhancement of IκBα and Anti-Inflammatory Cytokines. Inflammation 38, 846–857 (2015). https://doi.org/10.1007/s10753-014-9994-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-014-9994-y

KEY WORDS

Search

Navigation