Stilbenoids from the Melinjo (Gnetum gnemon L.) Fruit Modulate Cytokine Production in Murine Peyer's Patch Cells Ex Vivo

Abstract

Melinjo fruit (Gnetum gnemon L.) has been used as a food in Southeast Asia. To investigate if this fruit has regulatory actions on ileal immune responses, we measured T-helper (Th) cytokine production, i.e., interleukin-2 (IL-2), IL-4, IL-5, and interferon-gamma (IFN-γ), in cultured Peyer's patch (PP) cells from mice orally treated with a methanol extract of melinjo fruit. Oral administration of the 50 % ethanol extract at 100 mg/kg/day significantly enhanced the production of the Th1 cytokines IL-2 and IFN-γ irrespective of concanavalin-A stimulation, whereas the production of the Th2 cytokines IL-4 and IL-5 was not affected. We also isolated seven active constituents accompanied with two new stilbenoids from the ethylacetate fraction of the extracts. The structure of the new stilbene glucosides gnemonoside L (5) and gnemonoside M (7) was determined by 1D and 2D NMR and MS analyses. Five known stilbenoids were identified as resveratrol (1), isorhapontigenin (2), gnemonoside D (4), gnetins C (3) and E (6). Among these tested compounds, only new stilbenoid 7 strongly enhanced Th1 cytokine production in cultured PP cells at 10 mg/kg/day. These results indicated that this melinjo extract and its active constituent 7 potentiated T-cell-dependent immune responses in the ileal mucosa.

Gnetum gnemon L. - Gnetaceae - T‐helper - cytokine - Peyer's patch - stilbenoid

References

• 1 Eiseman F M. Fruits of Bari. Singapore; Periplus Edit 1988: 35
• 2 Kato E, Tokunaga Y, Sakan F. Stilbenoids isolated from the seeds of Melinjo (Gnetum gnemon L.) and their biological activity.  J Agric Food Chem. 2009;  57 2544-2549
• 3 Iliya I, Tanaka T, Iinuma M, Furusawa M, Ali Z, Nakaya K, Murata J, Darnaedi D. Five stilbene glucosides from Gnetum gnemonoides and Gnetum africanum.  Helv Chim Acta. 2002;  85 2395-2402
• 4 Iliya I, Tanaka T, Iinuma M, Ali Z, Furasawa M, Nakaya K. Dimeric stilbenes from stem lianas of Gnetum africanum.  Heterocycles. 2002;  57 1057-1062
• 5 Iliya I, Ali Z, Tanaka T, Iinuma M, Furusawa M, Nakaya K, Murata J, Darnaedi D. Stilbenoids from the stem of Gnetum latifolium (Gnetaceae).  Phytochemistry. 2002;  61 959-961
• 6 Tanaka T, Iliya I, Ito T, Furusawa M, Nakaya K I, Iinuma M, Shirataki Y, Matsuura N, Ubukata M, Murata J, Simozono F, Hirai K. Stilbenoids in lianas of Gnetum parvifolium.  Chem Pharm Bull. 2001;  49 858-862
• 7 Iliya I, Ali Z, Tanaka T, Iinuma M, Furusawa M, Nakaya K, Murata J, Darnaedi D, Matsuura N, Ubukata M. Stilbene derivatives from Gnetum gnemon Linn.  Phytochemistry. 2003;  62 601-606
• 8 Huang K S, Li R L, Wang Y H, Lin M. Three new stilbene trimers from the lianas of Gnetum hainanense.  Planta Med. 2001;  67 61-64
• 9 Ito T, Akao Y, Tanaka T, Iinuma M, Nozawa Y. Vaticanol C, a novel resveratrol tetramer, inhibits cell growth through induction of apoptosis in colon cancer cell lines.  Biol Pharm Bull. 2002;  25 147-148
• 10 Huang K S, Zhou S, Lin M, Wang Y H. An isorhapontigenin tetramer and a novel stilbene dimer from Gnetum hainanense.  Planta Med. 2002;  68 916-920
• 11 Nitta T, Arai T, Takamatsu H, Inatomi Y, Murata H, Iinuma M, Tanaka T, Ito T, Asai F, Iliya I, Nakanishi T, Watabe K. Antibacterial activity of extracts prepared from tropical and subtropical plants on methicillin-resistant Staphylococcus aureus.  J Health Sci. 2002;  48 273-276
• 12 Sakagami Y, Sawabe A, Komemushi S, All Z, Tanaka T, Iliya I, Iinuma M. Antibacterial activity of stilbene oligomers against vancomycin-resistant Enterococci (VRE) and methicillin-resistant Staphylococcus aureus (MRSA) and their synergism with antibiotics.  Biocontrol Sci. 2007;  12 7-14
• 13 de la Lastra C A, Villegas I. Resveratrol as an antioxidant and pro-oxidant agent: mechanisms and clinical implications.  Biochem Soc Trans. 2007;  35 (Pt. 5) 1156-1160
• 14 Hattori R, Otani H, Maulik N, Das D K. Pharmacological preconditioning with resveratrol: role of nitric oxide.  Am J Physiol Heart Circ Physiol. 2002;  282 H1988-H1995
• 15 Clarke J O, Mullin G E. A review of complementary and alternative approaches to immunomodulation.  Nutr Clin Pract. 2008;  23 49-62
• 16 Sartor R B. Innate immunity in the pathogenesis and therapy of IBD.  J Gastroenterol. 2003;  38 (Suppl. 15) 43-47
• 17 Nagata S, McKenzie C, Pender S L, Bajaj-Elliott M, Fairclough P D, Walker-Smith J A, Monteleone G, MacDonald T T. Human Peyer's patch T cells are sensitized to dietary antigen and display a Th cell type 1 cytokine profile.  J Immunol. 2000;  165 5315-5321
• 18 Prescott S L. Role of dietary immunomodulatory factors in the development of immune tolerance.  Nestle Nutr Workshop Ser Pediatr Program. 2009;  64 185-194
• 19 Takano F, Kikuchi Y, Fushiya S, Hojo H, Nozoe S, Yahagi N, Yahagi R, Kondo Y. The culture fluid of Isaira japonica Yasuda augments anti-sheep red blood cell antibody response in mice.  Biol Pharm Bull. 1996;  19 641-643
• 20 Takano F, Yahagi N, Yahagi R, Takada S, Yamaguchi M, Shoda S, Murase T, Fushiya S, Ohta T. The liquid culture filtrates of Paecilomyces tenuipes (Peck) Samson (= Isaria japonica Yasuda) and Paecilomyces cicadae (Miquel) Samson (= Isaria sinclairii (Berk.) Llond) regulate Th1 and Th2 cytokine response in murine Peyer's patch cells in vitro and ex vivo.  Int Immunopharmacol. 2005;  5 903-916
• 21 Matsumoto T, Yamada H. Orally administered Kampo (Japanese herbal) medicine, “Juzen-Taiho-To” modulates cytokine secretion in gut associated lymphoreticular tissues in mice.  Phytomedicine. 2000;  6 425-430
• 22 Takano F, Yamaguchi M, Takada S, Shoda S, Yahagi N, Takahashi T, Ohta T. Capsicum ethanol extracts and capsaicin enhance interleukin-2 and interferon-gamma production in cultured murine Peyer's patch cells ex vivo.  Life Sci. 2007;  80 1553-1563
• 23 Yamaguchi M, Hasegawa I, Yahagi N, Ishigaki Y, Takano F, Ohta T. Carotenoids modulate cytokine production in Peyer's patch cells ex vivo.  J Agric Food Chem. 2010;  58 8566-8572
• 24 Sato A, Iwasaki A. Peyer's patch dendritic cells as regulators of mucosal adaptive immunity.  Cell Mol Life Sci. 2005;  62 1333-1338
• 25 Lee J, Jung E, Lim J, Lee J, Hur S, Kim S S, Lim S, Hyun C G, Kim Y S, Park D. Involvement of nuclear factor-kappaB in the inhibition of pro-inflammatory mediators by pinosylvin.  Planta Med. 2006;  72 801-806
• 26 Li X M, Lin M, Wang Y H, Liu X. Four new stilbenoids from the lianas of Gnetum montanum f. megalocarpum.  Planta Med. 2004;  70 160-165
• 27 Neurath M F, Finotto S, Glimcher L H. The role of Th1/Th2 polarization in mucosal immunity.  Nat Med. 2002;  8 567-573