European Journal of Nutrition

, Volume 52, Issue 2, pp 505–512 | Cite as

Combined arginine and glutamine decrease release of de novo synthesized leukotrienes and expression of proinflammatory cytokines in activated human intestinal mast cells

  • Sandra Lechowski
  • Katharina Feilhauer
  • Ludger Staib
  • Moïse Coëffier
  • Stephan C. Bischoff
  • Axel LorentzEmail author
Original Contribution



Glutamine and arginine modulate inflammatory responses of epithelial cells and monocytes. Here, we studied the response of human mast cells to pharmacological doses of arginine and glutamine.


Mast cells isolated from intestinal tissue were incubated with physiological doses of arginine (0.1 mmol/L) and glutamine (0.6 mmol/L) or with pharmacological doses of arginine (2 mmol/L) and glutamine (10 mmol/L) for 18 h. Following stimulation by IgE receptor crosslinking mast cell mediators were measured by enzymatic assay, ELISA, multiplex bead immunoassay, or real-time RT-PCR, and activation of intracellular signaling molecules was determined using proteome profiler array or immunoblotting.


We found that the combined challenge of mast cells with pharmacological doses of arginine and glutamine caused a decrease in induced release of de novo synthesized leukotriene C4 but not of pre-stored β-hexosaminidase. Moreover, we found reduced expression of chemokines monocyte chemoattractant protein-1 (CCL2), macrophage inflammatory protein-1β (CCL4), IL-8 (CXCL8), and TNF in response to high doses of both amino acids. The anti-inflammatory effects of arginine and glutamine were associated with decreased activation levels of signaling molecules known to be involved in mast cell cytokine expression such as MAPK family members extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38, and the protein kinase B (Akt).


Arginine and glutamine attenuate IgE-dependent human mast cell activation by decreasing lipid mediator release and expression of proinflammatory cytokines.


Arginine Glutamine Intestinal mucosa Mast cell Cytokine expression 



The present work was supported by the Centre for Nutritional Medicine (ZEM 16AIII).

Conflict of interest

The authors declare that they have no conflict of interests.


  1. 1.
    Nieves C Jr, Langkamp-Henken B (2002) Arginine and immunity: a unique perspective. Biomed Pharmacother 56:471–482CrossRefGoogle Scholar
  2. 2.
    Powell-Tuck J (2007) Nutritional interventions in critical illness. Proc Nutr Soc 66:16–24CrossRefGoogle Scholar
  3. 3.
    Lecleire S, Hassan A, Marion-Letellier R, Antonietti M, Savoye G, Bole-Feysot C, Lerebours E, Ducrotte P, Dechelotte P, Coeffier M (2008) Combined glutamine and arginine decrease proinflammatory cytokine production by biopsies from Crohn’s patients in association with changes in nuclear factor-kappaB and p38 mitogen-activated protein kinase pathways. J Nutr 138:2481–2486CrossRefGoogle Scholar
  4. 4.
    Kolios G, Valatas V, Ward SG (2004) Nitric oxide in inflammatory bowel disease, a universal messenger in an unsolved puzzle. Immunology 113:427–437CrossRefGoogle Scholar
  5. 5.
    Suchner U, Heyland DK, Peter K (2002) Immune-modulatory actions of arginine in the critically ill. Br J Nutr 87(Suppl 1):121–132Google Scholar
  6. 6.
    Coeffier M, Marion-Letellier R, Dechelotte P (2010) Potential for amino acids supplementation during inflammatory bowel diseases. Inflamm Bowel Dis 16:518–524CrossRefGoogle Scholar
  7. 7.
    Chang WK, Yang KD, Chuang H, Jan JT, Shaio MF (2002) Glutamine protects activated human T cells from apoptosis by up-regulating glutathione and Bcl-2 levels. Clin Immunol 104:151–160CrossRefGoogle Scholar
  8. 8.
    Wischmeyer PE, Riehm J, Singleton KD, Ren H, Musch MW, Kahana M, Chang EB (2003) Glutamine attenuates tumor necrosis factor-alpha release and enhances heat shock protein 72 in human peripheral blood mononuclear cells. Nutrition 19:1–6CrossRefGoogle Scholar
  9. 9.
    Fukatsu K, Kudsk KA, Zarzaur BL, Wu Y, Hanna MK, DeWitt RC (2001) TPN decreases IL-4 and IL-10 mRNA expression in lipopolysaccharide stimulated intestinal lamina propria cells but glutamine supplementation preserves the expression. Shock 15:318–322CrossRefGoogle Scholar
  10. 10.
    Horio Y, Osawa S, Takagaki K, Hishida A, Furuta T, Ikuma M (2008) Glutamine supplementation increases Th1-cytokine responses in murine intestinal intraepithelial lymphocytes. Cytokine 44:92–95CrossRefGoogle Scholar
  11. 11.
    Boelens PG, Houdijk AP, Fonk JC, Nijveldt RJ, Ferwerda CC, Von Blomberg-Van Der Flier BM, Thijs LG, Haarman HJ, Puyana JC, Van Leeuwen PA (2002) Glutamine-enriched enteral nutrition increases HLA-DR expression on monocytes of trauma patients. J Nutr 132:2580–2586Google Scholar
  12. 12.
    Wells SM, Kew S, Yaqoob P, Wallace FA, Calder PC (1999) Dietary glutamine enhances cytokine production by murine macrophages. Nutrition 15:881–884CrossRefGoogle Scholar
  13. 13.
    Kretzmann NA, Fillmann H, Mauriz JL, Marroni CA, Marroni N, Gonzalez-Gallego J, Tunon MJ (2008) Effects of glutamine on proinflammatory gene expression and activation of nuclear factor kappa B and signal transducers and activators of transcription in TNBS-induced colitis. Inflamm Bowel Dis 14:1504–1513CrossRefGoogle Scholar
  14. 14.
    Coeffier M, Marion R, Leplingard A, Lerebours E, Ducrotte P, Dechelotte P (2002) Glutamine decreases interleukin-8 and interleukin-6 but not nitric oxide and prostaglandins e(2) production by human gut in vitro. Cytokine 18:92–97CrossRefGoogle Scholar
  15. 15.
    Coeffier M, Marion R, Ducrotte P, Dechelotte P (2003) Modulating effect of glutamine on IL-1beta-induced cytokine production by human gut. Clin Nutr 22:407–413CrossRefGoogle Scholar
  16. 16.
    Galli SJ, Grimbaldeston M, Tsai M (2008) Immunomodulatory mast cells, negative, as well as positive, regulators of immunity. Nat Rev Immunol 8:478–486CrossRefGoogle Scholar
  17. 17.
    Bischoff SC (2009) Physiological and pathophysiological functions of intestinal mast cells. Semin Immunopathol 31:185–205CrossRefGoogle Scholar
  18. 18.
    Rijnierse A, Nijkamp FP, Kraneveld AD (2007) Mast cells and nerves tickle in the tummy, implications for inflammatory bowel disease and irritable bowel syndrome. Pharmacol Ther 116:207–235CrossRefGoogle Scholar
  19. 19.
    He SH (2004) Key role of mast cells and their major secretory products in inflammatory bowel disease. World J Gastroenterol 10:309–318Google Scholar
  20. 20.
    Lilja I, Gustafson-Svard C, Franzen L, Sjodahl R (2000) Tumor necrosis factor-alpha in ileal mast cells in patients with Crohn’s disease. Digestion 61:68–76CrossRefGoogle Scholar
  21. 21.
    Sellge G, Bischoff SC (2006) Isolation, culture, and characterization of intestinal mast cells. Methods Mol Biol 315:123–138Google Scholar
  22. 22.
    Bischoff SC, Sellge G, Lorentz A, Sebald W, Raab R, Manns MP (1999) IL-4 enhances proliferation and mediator release in mature human mast cells. Proc Natl Acad Sci U S A 96:8080–8085CrossRefGoogle Scholar
  23. 23.
    Lorentz A, Schwengberg S, Sellge G, Manns MP, Bischoff SC (2000) Human intestinal mast cells are capable of producing different cytokine profiles, role of IgE receptor cross-linking and IL-4. J Immunol 164:43–48Google Scholar
  24. 24.
    Thienemann F, Henz BM, Babina M (2004) Regulation of mast cell characteristics by cytokines, divergent effects of interleukin-4 on immature mast cell lines versus mature human skin mast cells. Arch Dermatol Res 296:134–138CrossRefGoogle Scholar
  25. 25.
    Marion R, Coëffier MM, Gargala G, Ducrotté P, Déchelotte PP (2004) Glutamine and CXC chemokines IL-8, Mig, IP-10 and I-TAC in human intestinal epithelial cells. Clin Nutr 23:579–585CrossRefGoogle Scholar
  26. 26.
    Marion R, Coeffier M, Lemoulan S, Gargala G, Ducrotte P, Dechelotte P (2005) l-Arginine modulates CXC chemokines in the human intestinal epithelial cell line HCT-8 by the NO pathway. Biochimie 87:1048–1055CrossRefGoogle Scholar
  27. 27.
    Lecleire S, Coeffier M, Leblond J, Hubert A, Lemoulan S, Petit A, Ducrotte P, Dechelotte P, Marion R (2005) Modulation of nitric oxide and cytokines production by l-arginine in human gut mucosa. Clin Nutr 24:353–359CrossRefGoogle Scholar
  28. 28.
    Schwartz LB, Austen KF, Wasserman SI (1979) Immunologic release of beta-hexosaminidase and beta-glucuronidase from purified rat serosal mast cells. J Immunol 123:1445–1450Google Scholar
  29. 29.
    Feuser K, Feilhauer K, Staib L, Bischoff SC, Lorentz A (2011) Akt cross-links IL-4 priming, stem cell factor signaling, and IgE-dependent activation in mature human mast cells. Mol Immunol 48:546–552CrossRefGoogle Scholar
  30. 30.
    Lorentz A, Wilke M, Sellge G, Worthmann H, Klempnauer J, Manns MP, Bischoff SC (2005) IL-4-induced priming of human intestinal mast cells for enhanced survival and Th2 cytokine generation is reversible and associated with increased activity of ERK1/2 and c-Fos. J Immunol 174:6751–6756Google Scholar
  31. 31.
    Hubert-Buron A, Leblond J, Jacquot A, Ducrotte P, Dechelotte P, Coeffier M (2006) Glutamine pretreatment reduces IL-8 production in human intestinal epithelial cells by limiting IkappaBalpha ubiquitination. J Nutr 136:1461–1465Google Scholar
  32. 32.
    Mañé J, Fernández-Bañares F, Ojanguren I, Castellá E, Bertrán X, Bartolí R, Alvarez M, Gassull MA (2001) Effect of l-arginine on the course of experimental colitis. Clin Nutr 20:415–422CrossRefGoogle Scholar
  33. 33.
    Waetzig GH, Seegert D, Rosenstiel P, Nikolaus S, Schreiber S (2002) p38 mitogen-activated protein kinase is activated and linked to TNF-alpha signaling in inflammatory bowel disease. J Immunol 168:5342–5351Google Scholar
  34. 34.
    Lockyer HM, Tran E, Nelson BH (2007) STAT5 is essential for Akt/p70S6 kinase activity during IL-2-induced lymphocyte proliferation. J Immunol 179:5301–5308Google Scholar
  35. 35.
    Ruiz PA, Haller D (2006) Functional diversity of flavonoids in the inhibition of the proinflammatory NF-kappaB, IRF, and Akt signaling pathways in murine intestinal epithelial cells. J Nutr 136:664–671Google Scholar
  36. 36.
    Giris M, Erbil Y, Dogru-Abbasoglu S, Yanik BT, Alis H, Olgac V, Toker GA (2007) The effect of heme oxygenase-1 induction by glutamine on TNBS-induced colitis. Int J Colorectal Dis 22:591–599CrossRefGoogle Scholar
  37. 37.
    Coskun M, Olsen J, Seidelin JB, Nielsen OH (2011) MAP kinases in inflammatory bowel disease. Clin Chim Acta 412:513–520CrossRefGoogle Scholar
  38. 38.
    Neurath MF, Fuss I, Schurmann G et al (1998) Cytokine gene transcription by NF-kappa B family members in patients with inflammatory bowel disease. Ann N Y Acad Sci 859:149–159CrossRefGoogle Scholar
  39. 39.
    Schreiber S, Rosenstiel P, Hampe J, Nikolaus S, Groessner B, Schottelius A, Kuhbacher T, Hamling J, Folsch UR, Seegert D (2002) Activation of signal transducer and activator of transcription (STAT) 1 in human chronic inflammatory bowel disease. Gut 51:379–385CrossRefGoogle Scholar
  40. 40.
    Mudter J, Neurath MF (2007) IL-6 signaling in inflammatory bowel disease, pathophysiological role and clinical relevance. Inflamm Bowel Dis 13:1016–1023CrossRefGoogle Scholar
  41. 41.
    Levy DE, Darnell JE Jr (2002) Stats, transcriptional control and biological impact. Nat Rev Mol Cell Biol 3:651–662CrossRefGoogle Scholar
  42. 42.
    Koon HW, Zhao D, Zhan Y, Rhee SH, Moyer MP, Pothoulakis C (2006) Substance P stimulates cyclooxygenase-2 and prostaglandin E2 expression through JAK-STAT activation in human colonic epithelial cells. J Immunol 176:5050–5059Google Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Sandra Lechowski
    • 1
  • Katharina Feilhauer
    • 2
  • Ludger Staib
    • 3
  • Moïse Coëffier
    • 4
  • Stephan C. Bischoff
    • 1
  • Axel Lorentz
    • 1
    Email author
  1. 1.Department of Nutritional MedicineUniversity of HohenheimStuttgartGermany
  2. 2.Clinic for Visceral SurgeryKatharinen HospitalStuttgartGermany
  3. 3.Clinic for Visceral SurgeryKlinikum EsslingenEsslingenGermany
  4. 4.Appareil Digestif Environnement Nutrition ADEN EA4311, Institute for Biomedical Research, European Institute for Peptide Research (IFRMP 23)Rouen University and Rouen University HospitalRouen CedexFrance

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