Abstract
Branched chain amino acids are the essential nutrients for humans and many animals. As functional amino acids, they play important roles in physiological functions, including immune functions. Isoleucine, as one of the branched chain amino acids, is also critical in physiological functions of the whole body, such as growth, immunity, protein metabolism, fatty acid metabolism and glucose transportation. Isoleucine can improve the immune system, including immune organs, cells and reactive substances. Recent studies have also shown that isoleucine may induce the expression of host defense peptides (i.e., β-defensins) that can regulate host innate and adaptive immunity. In addition, isoleucine administration can restore the effect of some pathogens on the health of humans and animals via increasing the expression of β-defensins. Therefore, the present review will emphatically discuss the effect of isoleucine on immunity while summarizing the relationship between branched chain amino acids and immune functions.
Keywords: Isoleucine, branched chain amino acids, immune system, β-defensins, TLR/NF-κB pathway, ERK pathway.
Graphical Abstract
[1]
Nair, K.S.; Short, K.R. Hormonal and signaling role of branched-chain amino acids. J. Nutr., 2005, 135, 1547S-1552S.
[2]
Nie, C.; He, T.; Zhang, W.; Zhang, G.; Ma, X. Branched chain amino acids: Beyond nutrition metabolism. Int. J. Mol. Sci., 2018, 19E954
[3]
Ma, N.; Guo, P.; Zhang, J.; He, T.; Kim, S.W.; Zhang, G.; Ma, X. Nutrients mediate intestinal bacteria-mucosal immune crosstalk. Front. Immunol., 2018, 9, 5.
[4]
He, L.; Han, M.; Farrar, S.; Ma, X. Impacts and regulation of dietary nutrients on gut microbiome and immunity. Protein Pept. Lett., 2017, 24, 380-381.
[5]
Zhang, S.; Zeng, X.; Ren, M.; Mao, X.; Qiao, S. Novel metabolic and physiological functions of branched chain amino acids: A review. J. Anim. Sci. Biotechnol., 2017, 8, 10.
[6]
Newgard, C.B.; An, J.; Bain, J.R.; Muehlbauer, M.J.; Stevens, R.D.; Lien, L.F.; Haqq, A.M.; Shah, S.H.; Arlotto, M.; Slentz, C.A.; Rochon, J.; Gallup, D.; Ilkayeva, O.; Wenner, B.R.; Yancy, W.E.; Eisenson, H.; Musante, G.; Surwit, R.; Millington, D.S.; Butler, M.D.; Svetkey, L.P. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab., 2009, 9, 311-326.
[7]
Franco, D.J.; Josephson, J.K.; Moehn, S.; Pencharz, P.B.; Ball, R.O. Isoleucine requirement of pregnant sows. J. Anim. Sci., 2013, 91, 3859-3866.
[8]
Dong, X.Y.; Azzam, M.M.M.; Zou, X.T. Effects of dietary L-isoleu-cine on laying performance and immunomodulation of laying hens. Poult. Sci., 2016, 95, 2297-2305.
[9]
Olde Damink, S.W.; Jalan, R.; Deutz, N.E.; Dejong, C.H.; Redhead, D.N.; Hynd, P.; Hayes, P.C.; Soeters, P.B. Isoleucine infusion during “simulated” upper gastrointestinal bleeding improves liver and muscle protein synthesis in cirrhotic patients. Hepatology, 2007, 45, 560-568.
[10]
Appuhamy, J.A.; Knoebel, N.A.; Nayananjalie, W.A.; Escobar, J.; Hanigan, M.D. Isoleucine and leucine independently regulate mTOR signaling and protein synthesis in MAC-T cells and bovine mammary tissue slices. J. Nutr., 2012, 142, 484-491.
[11]
Zheng, C.T.; Li, D.F.; Qiao, S.Y.; Gong, L.M.; Zhang, D.F.; Thacker, P.; Han, I.K. Effects of isoleucine supplementation of a low protein, corn-soybean meal diet on the performance and immune function of weanling pigs. Asian-Australas. J. Anim. Sci., 2001, 14, 70-76.
[12]
Nishimura, J.; Masaki, T.; Arakawa, M.; Seike, M.; Yoshimatsu, H. Isoleucine prevents the accumulation of tissue triglycerides and upregulates the expression of PPARalpha and uncoupling protein in diet-induced obese mice. J. Nutr., 2010, 140, 496-500.
[13]
Du, Y.; Meng, Q.; Zhang, Q.; Guo, F. Isoleucine or valine deprivation stimulates fat loss via increasing energy expenditure and regulating lipid metabolism in WAT. Amino Acids, 2012, 43, 725-734.
[14]
Doi, M.; Yamaoka, I.; Nakayama, N.; Sugahara, K.; Yoshizawa, F. Hypoglycemic effect of isoleucine involves increased muscle glucose uptake and whole body glucose oxidation and decreased hepatic gluconeogenesis. Am. J. Physiol. Endocrinol. Metab., 2007, 292, E1683-E1693.
[15]
Zhang, S.; Yang, Q.; Ren, M.; Qiao, S.; He, P.; Li, D.; Zeng, X. Effects of isoleucine on glucose uptake through the enhancement of muscular membrane concentrations of GLUT1 and GLUT4 and intestinal membrane concentrations of Na+/glucose co-transporter 1 (SGLT-1) and GLUT2. Br. J. Nutr., 2016, 116, 593-602.
[16]
Kephart, W.C.; Wachs, T.D.; Mac Thompson, R.; Mobley, C.B.; Fox, C.D.; McDonald, J.R.; Ferguson, B.S.; Young, K.C.; Nie, B.; Martin, J.S.; Company, J.M.; Pascoe, D.D.; Arnold, R.D.; Moon, J.R.; Roberts, M.D. Ten weeks of branched chain amino acid supplementation improves select performance and immunological variables in trained cyclists. J. Int. Soc. Sports Nutr., 2015, 12, 20.
[17]
Nakamura, I. Impairment of innate immune responses in cirrhotic patients and treatment by branched-chain amino acids. World J. Gastroenterol., 2014, 20, 7298-7305.
[18]
Zhang, H.; Feng, F.; Wang, W.; Li, M.; Ji, G.; Guan, C. The effects
of BCAA-enriched amino acid solution on immune function and
protein metabolism in postoperative patients with rectal cancer.
Parenter. Enter. Nutr. 2007, 2, 009.
[19]
Ren, M.; Zhang, S.; Zeng, X.; Liu, H.; Qiao, S. Branched-chain amino acids are beneficial to maintain growth performance and intestinal immune-related function in weaned piglets fed protein restricted diet. Asian-Australas. J. Anim. Sci., 2015, 28, 1742-1750.
[20]
Xiao, W.; Chen, P.; Liu, X.; Zhao, L. The impaired function of macrophages induced by strenuous exercise could not be ameliorated by BCAA supplementation. Nutrients, 2015, 7, 8645-8656.
[21]
Coëffier, M.; Claeyssens, S.; Bensifi, M.; Lecleire, S.; Boukhettala, N.; Maurer, B.; Donnadieu, N.; Lavoinne, A.; Cailleux, A.F.; Déchelotte, P. Influence of leucine on protein metabolism, phosphokinase expression, and cell proliferation in human duodenum. Am. J. Clin. Nutr., 2011, 93, 1255-1262.
[22]
Mao, X.; Zeng, X.; Huang, Z.; Wang, J.; Qiao, S. Leptin and leucine synergistically regulate protein metabolism in C2C12 myotubes and mouse skeletal muscles. Br. J. Nutr., 2013, 110, 256-264.
[23]
Zhang, S.; Ren, M.; Zeng, X.; He, P.; Ma, X.; Qiao, S. Leucine stimulates ASCT2 amino acid transporter expression in porcine jejunal epithelial cell line (IPEC-J2) through PI3K/Akt/mTOR and ERK signaling pathways. Amino Acids, 2014, 46, 2633-2642.
[24]
Mao, X.; Hu, H.; Tang, J.; Chen, D.; Yu, B. Leucine increases mucin 2 and occludin production in LS174T cells partially via PI3K-Akt-mTOR pathway. Anim. Nutr., 2016, 2, 218-224.
[25]
Mao, X.; Liu, M.; Tang, J.; Chen, H.; Chen, D.; Yu, B.; He, J.; Yu, J.; Zheng, P. Dietary leucine supplementation improves the mucin production in the jejunal mucosa of the weaned pigs challenged by porcine rotavirus. PLoS One, 2015, 10e0137380
[26]
Mao, X.; Zeng, X.; Wang, J.; Qiao, S. Leucine promotes leptin re-ceptor expression in mouse C2C12 myotubes through the mTOR pathway. Mol. Biol. Rep., 2011, 38, 3201-3206.
[27]
Toneto, A.T.; Ramos, L.A.F.; Salomão, E.M.; Tomasin, R.; Aereas, M.A.; Gomes-marcondes, M.C.C. Nutritional leucine supplementation attenuates cardiac failure in tumour-bearing cachectic animals. J. Cachexia Sarcopenia Muscle, 2016, 7, 1-10.
[28]
Powell, J.D.; Pollizzi, K.N.; Heikamp, E.B.; Horton, M.R. Regulation of immune responses by mTOR. Annu. Rev. Immunol., 2012, 30, 39.
[29]
Soliman, G.A. The role of mechanistic target of rapamycin (mTOR) complexes signaling in the immune responses. Nutrients, 2013, 5, 2231-2257.
[30]
Jiang, W.; Deng, Y.; Liu, Y.; Qu, B.; Jiang, J.; Kuang, S.; Tang, L.; Tang, W.; Wu, P.; Zhang, Y.; Zhou, X.; Feng, L. Dietary leucine regulates the intestinal immune status, immune-related signalling molecules and tight junction transcript abundance in grass carp (Ctenopharyngodon idella). Aquaculture, 2015, 444, 134-142.
[31]
Uyangaa, E.; Lee, H.; Eo, S.K. Glutamine and leucine provide enhanced protective immunity against mucosal infection with Herpes Simplex Virus Type 1. Immune Netw., 2012, 12, 196-206.
[32]
Luo, J.B.; Feng, L.; Jiang, W.D.; Liu, Y.; Wu, P.; Jiang, J.; Kuang, S.Y.; Tang, L.; Zhang, Y.A.; Zhou, X.Q. The impaired intestinal mucosal immune system by valine deficiency for young grass carp (Ctenopharyngodon idella) is associated with decreasing immune status and regulating tight junction proteins transcript abundance in the intestine. Fish Shellfish Immunol., 2014, 40, 197-207.
[33]
Kakazu, E.; Kanno, N.; Ueno, Y.; Shimosegawa, T. Extracellular branched-chain amino acids, especially valine, regulate maturation and function of monocyte-derived dendritic cells. J. Immunol., 2007, 179, 7137-7146.
[34]
Thornton, S.A.; Corzo, A.; Pharr, G.T.; Dozier Iii, W.A.; Miles, D.M.; Kidd, M.T. Valine requirements for immune and growth responses in broilers from 3 to 6 weeks of age. Br. Poult. Sci., 2006, 47, 190-199.
[35]
Hale, L.L.; Pharr, G.T.; Burgess, S.C.; Corzo, A.; Kidd, M.T. Isoleucine needs of thirty- to forty-day-old female chickens: immunity. Poult. Sci., 2004, 83, 1979-1985.
[36]
Aschkenasy, A. Dietary proteins and amino acids in leucopoiesis: recent hematological and immunological data. World Rev. Nutr. Diet., 1975, 21, 151-197.
[37]
Petro, T.M.; Bhattacharjee, J.K. Effect of dietary essential amino acid limitations upon the susceptibility to Salmonella typhimurium and the effect upon humoral and cellular immune responses in mice. Infect. Immun., 1981, 32, 251-259.
[38]
Gong, B.; Ren, M.; Jin, E.; Li, Q.; Li, X.; Li, S. . Effect of isoleucine
on the serum antioxidant levels and the structure of spleen in rats.
J. Anhui. Sci. Technol. Univ. , 2015; 29, pp. 1-5.
[39]
Burns, C.P. Isoleucine metabolism by leukemic and normal human leukobytes in relation to cell maturity and type. Blood, 1975, 45, 643-651.
[40]
Chuang, J.C.; Yu, C.L.; Wang, S.R. Modulation of human lymphocyte proliferation by amino acids. Clin. Exp. Immunol., 1990, 81, 173-176.
[41]
Waithe, W.I.; Dauphinais, C.; Hathaway, P.; Hirschhorn, K. Protein synthesis in stimulated lymphocytes. II. Amino acid requirements. Cell. Immunol., 1975, 17, 323-334.
[42]
Rivas-Santiago, C.E.; Rivas-Santiago, B.; León, D.A.; Castañeda-Delgado, J.; Hernández Pando, R. Induction of β-defensins by L-isoleucine as novel immunotherapy in experimental murine tuberculosis. Clin. Exp. Immunol., 2011, 164, 80-89.
[43]
Ren, M. Branched-chain amino acids modulate intestinal defensing expression and immune barrier function of piglets., PhD Thesis,
China Agricultural University: Beijing, June. 2014.
[44]
Huang, Z.; Zhou, C.; Lin, H.; Tan, X.; Peng, J.; Zhou, W.; Zhao, S.; Qi, C. (2017). Effects of dietary isoleucine levels on activities of digestive enzymes and immune index of Trachinotus ovatus. South China Fisheries Sci, 2017, 13, 50-57.
[45]
Feng, L.; Gan, L.; Jiang, W.D.; Wu, P.; Liu, Y.; Jiang, J.; Tang, L.; Kuang, S.Y.; Tang, W.N.; Zhang, Y.A.; Zhou, X.Q. Gill structural integrity changes in fish deficient or excessive in dietary isoleucine: Towards the modulation of tight junction protein, inflammation, apoptosis and antioxidant defense via NF-κB, TOR and Nrf2 signaling pathways. Fish Shellfish Immunol., 2017, 63, 127-138.
[46]
Zhao, J.; Feng, L.; Liu, Y.; Jiang, W.; Wu, P.; Jiang, J.; Zhang, Y.; Zhou, X. Effect of dietary isoleucine on the immunity, antioxidant status, tight junctions and microflora in the intestine of juvenile Jian carp (Cyprinus carpio var. Jian). Fish Shellfish Immunol., 2014, 41, 663-673.
[47]
Zhao, J.; Liu, Y.; Jiang, J.; Wu, P.; Jiang, W.; Li, S.; Tang, L.; Kuang, S.; Feng, L.; Zhou, X. Effects of dietary isoleucine on the immune response, antioxidant status and gene expression in the head kidney of juvenile Jian carp (Cyprinus carpio var. Jian). Fish Shellfish Immunol., 2013, 35, 572-580.
[48]
Mao, X.; Gu, C.; Ren, M.; Chen, D.; Yu, B.; He, J.; Yu, J.; Zheng, P.; Luo, J.; Wang, J.; Tian, G.; Yang, Q. L-isoleucine administration alleviates rotavirus infection and immune response in the weaned piglet model. Front. Immunol., 2018, 9, 1654.
[49]
Lyu, W.; Curtis, A.R.; Sunkara, L.T.; Zhang, G. Transcriptional regulation of antimicrobial host defense peptides. Curr. Protein Pept. Sci., 2015, 16, 672-679.
[51]
Brown, K.L.; Hancock, R.E. Cationic host defense (antimicrobial) peptides. Curr. Opin. Immunol., 2006, 18, 24-30.
[52]
Zhang, G.; Sunkara, L.T.A. vian antimicrobial host defense peptides: from biology to therapeutic applications. Pharmaceuticals (Basel), 2014, 7, 220-247.
[53]
Selsted, M.E.; Ouellette, A.J. Mammalian defensins in the antimicrobial immune response. Nat. Immunol., 2005, 6, 551-557.
[54]
Mao, X.; Qi, S.; Yu, B.; He, J.; Yu, J.; Chen, D. Zn2+ and L-isoleucine induce the expressions of porcine β-defensins in IPEC-J2 cells. Mol. Biol. Rep., 2013, 40, 1547-1552.
[55]
Ren, M.; Zhang, S.; Liu, X.; Li, S.; Mao, X.; Zeng, X.; Qiao, S. Different lipopolysaccharide branched-chain amino acids modulate porcine intestinal endogenous β-defensin expression through the Sirt1/ERK/90RSK pathway. J. Agric. Food Chem., 2016, 64, 3371-3379.
[56]
Sherman, H.; Chapnik, N.; Froy, O. Albumin and amino acids upregulate the expression of human beta-defensin 1. Mol. Immunol., 2006, 43, 1617-1623.
[57]
Konno, Y.; Ashida, T.; Inaba, Y.; Ito, T.; Tanabe, H.; Maemoto, A.; Ayabe, T.; Mizukami, Y.; Fujiya, M.; Kohgo, Y. Isoleucine, an essential amino acid, induces the expression of human β defensin 2 through the activation of the G-protein coupled receptor-ERK pathway in the intestinal epithelia. Food Nutr. Sci., 2012, 3, 548-555.
[58]
Fehlbaum, P.; Rao, M.; Zasloff, M.; Anderson, G.M. An essential amino acid induces epithelial β-defensin expression. Proc. Natl. Acad. Sci. USA, 2000, 97, 12723-12728.
[59]
Foureau, D.M.; Mielcarz, D.W.; Menard, L.C.; Schulthess, J.; Werts, C.; Vasseur, V.; Ryffel, B.; Kasper, L.H.; Buzoni-Gatel, D. TLR9-dependent induction of intestinal alpha-defensins by Toxoplasma gondii. J. Immunol., 2010, 184, 7022-7029.
[60]
Alam, N.H.; Ashraf, H.; Gyr, N.E.; Meier, R.F. Evaluation of the efficacy of L-isoleucine and L-arginine supplemented food in the treatment of acute diarrhea in malnourished children. Gastroenterology, 2013, 144, S566-S567.
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