Umbelliprenin induced both anti-inflammatory and regulatory cytokines in C57/BL6 mice

Document Type: Original Article

Authors

1 Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran

2 Department of Immunology, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran

3 Shiraz Institute for Cancer Research, Shiraz University of Medical Sciences, Shiraz, Iran

4 Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

5 Department of Pathology, Shiraz University of Medical Sciences, Shiraz, Iran

6 Department of Immunology, Shiraz University of Medical Sciences, Shiraz, Iran

Abstract

Objective(s): Umbelliprenin is a prenyloxy-coumarin with pharmacologically polyvalent activity. Several studies have shown its anti-inflammatory, anti-tumor, antioxidant, and antigenotoxic activity, and other functions. However, the exact mechanism of action of this compound on the immune response has not yet been shown. Here, we investigated umbelliprenin effects on the predominance of Th1 and Th2 responses in normal C57/BL6 mice.
Materials and Methods: Umbelliprenin (2.5 mg/200 µl IP) were administered to six C57/BL6 mice every other day for 8 days. Paraffin and PBS-injected mice were enrolled as solvent and control groups, respectively (n=6 mice/group). IL-10, IFN-γ, and IL-4 levels were determined in sera and also in splenocytes culture supernatants in the presence of Con A (3 µg/ml) after 72 hr. H&E staining of paraffin embedded blocks was performed for lung and liver tissues of mice.
Results: Umbelliprenin could significantly increase the secretion of IFN-γ and IL-4 in sera and IL-10 in splenocytes cultures. Comparison of IFN-γ /IL-4 in the sera and splenocytes culture supernatants showed lower ratios in umbelliprenin treated mice than in solvent and untreated groups.
Conclusion: The in vivo study showed that umbelliprenin could induce anti-inflammatory responses via the predominance of Th2 cells and some regulatory responses in C57/BL6 mice.

Keywords


1. Iranshahi M, Shahverdi AR, Mirjani R, Amin G, Shafiee A. Umbelliprenin from Ferula persica roots inhibits the red pigment production in Serratia marcescens. Z Naturforsch C 2004; 59:506-508.

2. Iranshahi M, Arfa P, Ramezani M, Jaafari MR, Sadeghian H, Bassarello C, et al. Sesquiterpene coumarins from Ferula szowitsiana and in vitro antileishmanial activity of 7-prenyloxycoumarins against promastigotes. Phytochemistry 2007; 68:554-561.

3. Askari M, Sahebkar A, Iranshahi M. Synthesis and purification of 7-prenyloxycoumarins and herniarin as bioactive natural coumarins. Iran J Basic Med Sci 2009; 12:63-69.

4. Barthomeuf C, Lim S, Iranshahi M, Chollet P. Umbelliprenin from Ferula szowitsiana inhibits the growth of human M4Beu metastatic pigmented malignant melanoma cells through cell-cycle arrest in G1 and induction of caspase-dependent apoptosis. Phytomedicine 2008; 15:103-111.

5. Ziai SA, Gholami O, Iranshahi M, Zamani AH, Jeddi-Tehrani M. Umbelliprenin induces apoptosis in CLL cell lines. Iran J Pharm Res 2012; 11:653-659.

6. Khaghanzadeh N, Mojtahedi Z, Ramezani M, Erfani N, Ghaderi A. Umbelliprenin is cytotoxic against QU-DB large cell lung cancer cell line but anti-proliferative against A549 adenocarcinoma cells. DARU 2012; 20:69.

7. Iranshahi M, Sahebkar A, Takasaki M, Konoshima T, Tokuda H. Cancer chemopreventive activity of the prenylated coumarin, umbelliprenin, in vivo. Eur J Cancer Prev 2009; 18:412-415.

8. Khaghanzadeh N, Samiei A, Ramezani M, Mojtahedi Z, Hosseinzadeh M, Ghaderi A. Umbelliprenin induced production of IFN-gamma and TNF-alpha, and reduced IL-10, IL-4, Foxp3 and TGF-beta in a mouse model of lung cancer. Immunopharmcol Immunotoxicol 2014; 36:25-32.

9. Iranshahi M, Askari M, Sahebkar A, Hadjipavlou-Litina D. Evaluation of antioxidant, anti-inflammatory and lipoxygenase inhibitory activities of the prenylated coumarin umbelliprenin. DARU 2009; 17:99-103.

10. Shahverdi AR, Saadat F, Khorramizadeh MR, Iranshahi M, Khoshayand MR. Two matrix metalloproteinases inhibitors from Ferula persica var. persica. Phytomedicine 2006; 13:712-717.

11. Bayrami G, Boskabady MH, Iranshahi M, Gholamnezhad Z. Relaxant effects of asafoetida extract and its constituent umbelliprenin on guinea-pig tracheal smooth muscle. Chin J Integr Med 2013.

12. Tanaka T, Sugiura H, Inaba R, Nishikawa A, Murakami A, Koshimizu K, et al. Immunomodulatory action of citrus auraptene on macrophage functions and cytokine production of lymphocytes in female BALB/c mice. Carcinogenesis 1999; 20:1471-1476.

13. Niu X, Huang Z, Zhang L, Ren X, Wang J. Auraptene has the inhibitory property on murine T lymphocyte activation. Eur J Pharmacol 2015; 750:8-13.

14. Gholami O, Shamsara J. Comparison of the cytotoxic effects of umbelliprenin and auraptene. Int J Pharm Pharm Sci 2016; 8:1-4.

15. Akhila JS, Shyamjith, Deepa, Alwar MC. Acute toxicity studies and determination of median lethal dose. Curr Sci 2007; 93:917-920.

16. Taboas JO, Ceremsak RJ. A rapid hematoxylin and eosin stain. Tech Bull Regist Med Technol 1967; 37:119-120.

17. Abbas AK, Lichtman AH, Pillai S. Cytokines. In: Cellular and Molecular Immunology. 6th ed. Saunders; an imprint of Elsevier Inc; 2007. p. 267-302.

18. Zaidi MR, Merlino G. The two faces of interferon-gamma in cancer. Clin Cancer Res 2011; 17:6118-6124.

19. Ho MY, Tang SJ, Sun KH, Yang W. Immunotherapy for lung cancers. J Biomed Biotechnol 2011; 2011:250860.

20. Njoku DB. Suppressive and pro-inflammatory roles for IL-4 in the pathogenesis of experimental drug-induced liver injury: a review. Expert Opin Drug Metab Toxicol 2010; 6:519-531.

21. Pierson W, Liston A. A new role for interleukin-10 in immune regulation. Immunol Cell Biol 2010; 88:769-770.

22. Han S, Asoyan A, Rabenstein H, Nakano N, Obst R. Role of antigen persistence and dose for CD4+ T-cell exhaustion and recovery. Proc Natl Acad Sci U S A 2010; 107:20453-20458.

23. Cope A, Le Friec G, Cardone J, Kemper C. The Th1 life cycle: molecular control of IFN-gamma to IL-10 switching. Trends Immunol 2011; 32:278-286.

24. Jaruga B, Hong F, Sun R, Radaeva S, Gao B. Crucial role of IL-4/STAT6 in T cell-mediated hepatitis: up-regulating eotaxins and IL-5 and recruiting leukocytes. J Immunol 2003; 171:3233-3244.

25. Shakeri A, Iranshahy M, Iranshahi M. Biological properties and molecular targets of umbelliprenin--a mini-review. J Asian Nat Prod Res 2014; 16:884-889.

26. Li G, Li X, Cao L, Zhang L, Shen L, Zhu J, et al. Sesquiterpene coumarins from seeds of Ferula sinkiangensis. Fitoterapia 2015; 103:222-226.

27. Khorramizadeh MR, Esmail-Nazari Z, Zarei-Ghaane Z, Shakibaie M, Mollazadeh-Moghaddam K, Iranshahi M, et al. Umbelliprenin-coated Fe3O4 magnetite nanoparticles: Antiproliferation evaluation on human Fibrosarcoma cell line (HT-1080). Materials Sci Eng C Mater  Biol Appl 2010; 30:1038-1042.