Isoleucine, an Essential Amino Acid, Induces the Expression of Human <i>β</i> Defensin 2 through the Activation of the G-Protein Coupled Receptor-ERK Pathway in the Intestinal Epithelia — Oak Academic Publishing
Research ArticleOpen AccessGoogle Scholar indexed
Isoleucine, an Essential Amino Acid, Induces the Expression of Human <i>β</i> Defensin 2 through the Activation of the G-Protein Coupled Receptor-ERK Pathway in the Intestinal Epithelia
Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
,
IBD Center, Sapporo Higashi Tokushukai Hospital, Sapporo, Japan
,
Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
,
Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
,
Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
,
IBD Center, Sapporo Higashi Tokushukai Hospital, Sapporo, Japan
,
Innate Immunity Laboratory, Department of Cellular Life Science, Faculty of Advanced Life Science, Hokkaido University, Sapporo, Japan
,
Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
,
Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
,
Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
1 Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
2 IBD Center, Sapporo Higashi Tokushukai Hospital, Sapporo, Japan
3 Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
4 Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
5 Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
6 IBD Center, Sapporo Higashi Tokushukai Hospital, Sapporo, Japan
7 Innate Immunity Laboratory, Department of Cellular Life Science, Faculty of Advanced Life Science, Hokkaido University, Sapporo, Japan
8 Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
9 Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
10 Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
Anti-microbial peptides are essential for the intestinal innate immunity that protects the intestinal epithelia from attacks by foreign pathogens. Human β -defensin (HBD) is one of the pivotal anti-microbial peptides that are expressed in the colonic epithelia. This study investigated the effect and the signaling mechanism of inducible β -defensin HBD2 by an essential amino acid, isoleucine (Ile) in colonic epithelial cells. Here we examined the expression level of HBD2 on induction of Ile in epithelial cells, and checked this pathway. HBD2 mRNA was induced by co-incubation with IL-1 α and Ile in Caco2 cells, but not by Ile alone. An inhibitor of either ERK or Gi, a subunit of G-proteins, reduced the induction of HBD2 mRNA by Ile. The treatment with Ile also increased the intracellular calcium ion concentration, thus suggesting that the GPCR and ERK signaling pathway mediate the effects of Ile. These results indicate that an essential amino acid, Ile, enhances the expression of an inducible β -defensin, namely HBD2, by IL-1 α through the activation of GPCRs and ERK signaling pathway. The administration of Ile may therefore represent a possible option to safely treat intestinal inflammation.
M. Zasloff, “Antimicrobial Peptides of Multicellular Organisms,” Nature, Vol. 415, No. 6870, 2001, pp. 389395.doi:10.1038/415389a
N. H. Salzman, D. Ghosh, K. M. Huttner, Y. Paterson and C. L. Bevins, “Protection against Enteric Salmonellosis in Transgenic Mice Expressing a Human Intestinal Defensing,” Nature, Vol. 422, No. 6931, 2003, pp. 522-526. doi:10.1038/nature01520
T. Ayabe, D. P. Satchell, C. L. Wilson, W. C. Parks, M. E. Selsted and A. J. Ouellette, “Secretion of Microbicidal Alpha-Defensins by Intestinal Paneth Cells in Response to Bacteria,” Nature Immunology, Vol. 1, No. 2, 2000, pp. 113-118. doi:10.1038/77783
A. J. Ouellette, “Paneth Cell Alpha-Defensins: Peptide Mediators of Innate Immunity in the Small Intestine,” Springer Seminars in Immunopathology, Vol. 27, No. 2, 2005, pp. 133-146. doi:10.1007/s00281-005-0202-x
J. Wehkamp, N. H. Salzman, E. Porter, S. Nuding, M. Weichenthal, R. E. Petras, B. Shen, E. Schaeffeler, M. Schwab, R. Linzmeier, R. W. Feathers, H. Chu, H. Lima Jr., K. Fellermann, T. Ganz, E. F. Stange and C. L. Bevins, “Reduced Paneth Cell Alpha-Defensins in Ileal Crohn’s Disease,” The Proceedings of the National Academy of Sciences USA, Vol. 102, No. 50, 2005, pp. 1812918134. doi:10.1073/pnas.0505256102
M. N. Becker, G. Diamond, M. W. Verghese and S. H. Randell, “CD14-Dependent Lipopolysaccharide-Induced Beta-Defensin-2 Expression in Human Tracheobronchial Epithelium,” The Journal of Biological Chemistry, Vol. 275, No. 38, 2000, pp. 29731-29736. doi:10.1074/jbc.M000184200
C. Fulton, G. M. Anderson, M. Zasloff, R. Bull and A. G. Quinn, “Expression of Natural Peptide Antibiotics in Human Skin,” Lancet, Vol. 350, 1997, pp. 1750-1751. doi:10.1016/S0140-6736(05)63574-X
H. P. Jia, B. C. Schutte, A. Schudy, R. Linzmeier, J. M. Guthmiller, G. K. Johnson, B. F. Tack, J. P. Mitros, A. Rosenthal, T. Ganz and P. B. McCray Jr., “Discovery of New Human Beta-Defensins Using a Genomics-Based Approach,” Gene, Vol. 263, No. 1-2, 2001, pp. 211-218. doi:10.1016/S0378-1119(00)00569-2
P. K. Singh, H. P. Jia, K. Wiles, J. Hesselberth, L. Liu, B. A. Conway, E. P. Greenberg, E. V. Valore, M. J. Welsh, T. Ganz, B. F. Tack and P. B. McCray Jr., “Production of Beta-Defensins by Human airway Epithelia,” The Proceedings of the National Academy of Sciences USA, Vol. 95, No. 25, 1998, pp. 14961-14966. doi:10.1073/pnas.95.25.14961
O. E. Sorensen, D. R. Thapa, A. Rosenthal, L. Liu, A. A. Roberts and T. Ganz, “Differential Regulation of BetaDefensin Expression in Human Skin by Microbial Stimuli,” The Journal of Immunology, Vol. 74, No. 8, 2005, pp. 4870-4879.
A. Y. Liu, D. Destoumieux, A. V. Wong, C. H. Park, E. V. Valore, L. Liu and T. Ganz, “Human-Defensin-2 Production in Keratinocytes Is Regulated by Interleukin-1, Bacteria, and the State of Differentiation,” Journal of Investigative Dermatology , Vol. 118, 2002, pp. 275-281. doi:10.1046/j.0022-202x.2001.01651.x
Y. Tsutsumi-Ishii and I. Nagaoka, “Modulation of Human β-Defensin-2 Transcription in Pulmonary Epithelial Cells by Lipopolysaccharide-Stimulated Mononuclear Phagocytes via Proinflammatory Cytokine Production,” The Journal of Immunology, Vol. 170, 2003, p. 4226.
J. Harder, J. Bartels, E. Christophers and J. M. Schroder, “Isolation and Characterization of Human β-Defensin-3, a Novel Human Inducible Peptide Antibiotic,” The Journal of Biological Chemistry, Vol. 276, No. 51, 2001, pp. 5707-5713. doi:10.1074/jbc.M008557200
J. Wehkamp, J. Harder, M. Weichenthal, O. Mueller, K. R. Herrlinger, K. Fellermann, J. M. Schroeder and E. F. Stange, “Inducible and Constitutive β-Defensins Are Differentially Expressed in Crohn’s Disease and Ulcerative Colitis,” Inflammatory Bowel Diseases, Vol. 9, No. 4, 2003, pp. 215-223. doi:10.1097/00054725-200307000-00001
J. P. Hugot, M. Chamaillard, H. Zouali, S. Lesage, J. P. Cézard, J. Belaiche, S. Almer, C. Tysk, C. A. O’Morain, M. Gassull, V. Binder, Y. Finkel, A. Cortot, R. Modigliani, P. Laurent-Puig, C. Gower-Rousseau, J. Macry, J. F. Colombel, M. Sahbatou and G. Thomas, “Association of NOD2 Leucine-Rich Repeat Variants with Susceptibility to Crohn’s Disease,” Nature, Vol. 411, No. 6837, 2001, pp. 599-603. doi:10.1038/35079107
P. Fehlbaum, M. Rao, M. Zasloff and G. M. Anderson, “An Essential Amino Acid Induces Epithelial Beta-Defensin Expression,” The Proceedings of the National Academy of Sciences USA, Vol. 97, No. 23, 2000, pp. 1272312728. doi:10.1073/pnas.220424597
S. K. Moon, H. Y. Lee, J. D. Li, M. Nagura, S. H. Kang, Y. M. Chun, F. H. Linthicum, T. Ganz, A. Andalibi and D. J. Lim, “Activation of a Src-Dependent Raf-MEK1/2ERK Signaling Pathway Is Required for IL-1a-Induced Upregulation of h-Defensin 2 in Human Middle Ear Epithelial Cells,” Biochimica et Biophysica Acta, Vol. 1590, No. 1-3, 2002, pp. 41-51. doi:10.1016/S0167-4889(02)00196-9
C. Bezencxon, J. le Coutre and S. Damak, “Taste-Signaling Proteins Are Coexpressed in Solitary Intestinal Epithelial Cells,” Chemical Senses, Vol. 32, No. 1, 2007, pp. 41-49. doi:10.1093/chemse/bjl034
S. Okumura, H. Baba, T. Kumada, K. Nanmoku, H. Nakajima, Y. Nakane, K. Hioki and K. Ikenaka, “Cloning of a G-Protein-Coupled Receptor That Shows an Activity to Transform NIH3T3 Cells and Is Expressed in Gastric Cancer Cells,” Cancer Science, Vol. 95, No. 2, 2004, pp. 131-135. doi:10.1111/j.1349-7006.2004.tb03193.x
B. F. O’Dowd, T. Nguyen, A. Marchese, R. Cheng, K. R. Lynch, H. H. Heng, L. F. Kolakowski Jr. and S. R. George, “Discovery of Three Novel G-Protein-Coupled Receptor Genes,” Genomics, Vol. 47, No. 15, 1998, pp. 310-313. doi:10.1006/geno.1998.5095
M. Wan, A. Sabirsh, A. Wetterholm, B. Agerberth and J. Z. Haeggstrom, “Leukotriene B4 Triggers Release of the Cathelicidin LL-37 from Human Neutrophils: Novel LipidPeptide Interactions in Innate Immune Responses,” The FASEB Journal, Vol. 21, No. 11, 2007, pp. 2897-2905. doi:10.1096/fj.06-7974com
H. Dommisch, W. O. Chung, M. G. Rohani, D. Williams, M. Rangarajan, M. A. Curtis and B. A. Dale, “ProteaseActivated Receptor 2 Mediates Human Beta-Defensin 2 and CC Chemokine Ligand 20 mRNA Expression in Response to Proteases Secreted by Porphyromonas gingivalis,” Infection and Immunity, Vol. 75, No. 9. 2007, pp. 43264333. doi:10.1128/IAI.00455-07
L. R. Howe and C. J. Marshall, “Lysophosphatidic Acid Stimulates Mitogen-Activated Protein Kinase Activation via a G-Protein-Coupled Pathway Requiring p21ras and p74raf-1,” The Journal of Biological Chemistry, Vol. 268, No. 28, 1993, pp. 20717-20720.
P. L. Hordijk, I. Verlaan, E. J. van Corven and W. H. Moolenaar, “Protein Tyrosine Phosphorylation Induced by Lysophosphatidic Acid in Rat-1 Fibroblasts. Evidence that Phosphorylation of Map Kinase Is Mediated by the Gi-p21ras Pathway,” The Journal of Biological Chemistry, Vol. 269, No. 1, 1994, pp. 645-651.
V. J. LaMorte, E. D. Kennedy, L. R. Collins, D. Goldstein, A. T. Harootunian, J. H. Brown and J. R. Feramisco, “A Requirement for Ras Protein Function in ThrombinStimulated Mitogenesis in Astrocytoma Cells,” The Journal of Biological Chemistry, Vol. 268, No. 26, 1993, pp. 19411-19415.
J. E. Duff, B. C. Berk and M. A. Corson, “Angiotensin II Stimulates the pp44 and pp42 Mitogen-Activated Protein Kinases in Cultured Rat Aortic Smooth Muscle Cells,” Biochemical and Biophysical Research Communications, Vol. 188, No. 1, 1992, pp. 257-264. doi:10.1016/0006-291X(92)92378-B
Y. Ishida, Y. Kawahara, T. Tsuda, M. Koide and M. Yokoyama, “Involvement of MAP Kinase Activators in Angiotensin II-Induced Activation of MAP Kinases in Cultured Vascular Smooth Muscle Cells,” FEBS Letters, Vol. 310, No. 1, 1992, pp. 41-45. doi:10.1016/0014-5793(92)81142-9
B. E. Hawes, T. van Biesen, W. J. Koch, L. M. Luttrell and R. J. Lefkowitz, “Distinct Pathways of Giand GqMediated Mitogen-Activated Protein Kinase Activation,” The Journal of Biological Chemistry, Vol. 270, 1995, pp. 17148-17153. doi:10.1074/jbc.270.29.17148
T. van Biesen, B. E. Hawes, D. K. Luttrell, K. M. Krueger, K. Touhara, E. Porfiri, M. Sakaue, L. M. Luttrell, and R. J. Lefkowitz, “Receptor-Tyrosine-Kinaseand G Beta Gamma-Mediated MAP Kinase Activation by a Common Signalling Pathway,” Nature, Vol. 376, No. 6543, 1995, pp. 781-784. doi:10.1038/376781a0
V. Mieulet, L. Yan, C. Choisy, K. Sully, J. Procter, A. Kouroumalis, S. Krywawych, M. Pende, S. C. Ley, C. Moinard and R. F. Lamb, “TPL-2-Mediated Activation of MAPK Downstream of TLR4 Signaling Is Coupled to Arginine Availability,” Science Signaling, Vol. 3, No. 135, 2010, p. ra61. doi:10.1126/scisignal.2000934
S. K. Moon, H. Y. Lee, J. D. Li, M. Nagura, S. H. Kang, Y. M. Chun, F. H. Linthicum, T. Ganz, A. Andalibi and D. J. Lim, “Activation of a Src-Dependent Raf-MEK1/2ERK Signaling Pathway Is Required for IL-1a-Induced Upregulation of h-Defensin 2 in Human Middle Ear Epithelial Cells,” Biochimica et Biophysica Acta, Vol. 1590, No. 1-3, 2002, pp. 41-51. doi:10.1016/S0167-4889(02)00196-9
N. Wettschureck and S. Offermanns, “Mammalian G Proteins and Their Cell Type Specific Functions,” Physiological Reviews, Vol. 85, No. 4, 2005, pp. 1159-1204. doi:10.1152/physrev.00003.2005
Y. Chen-Izu, R. P. Xiao, L.T. Izu, H. Cheng, M. Kuschel, H. Spurgeon and E. G. Lakatta, “G(i)-Dependent Localization of Beta(2)-Adrenergic Receptor Signaling to LType Ca(2+) Channels,” Biophysical Journal, Vol. 79, No. 5, 2000, pp. 2547-2556. doi:10.1016/S0006-3495(00)76495-2
H. J. Lee, H. C. Mun, N. C. Lewis, M. F. Crouch, E. L. Culverston, R. S. Mason and A. D. Conigrave, “Allosteric Activation of the Extracellular Ca2+-Sensing Receptor by L-Amino Acids Enhances ERK1/2 Phosphorylation,” Biochemical Journal, Vol. 404, Part 1, 2007, pp. 141-149. doi:10.1042/BJ20061826
T. Witth?ft, C. S. Pilz, K. Fellermann, M. Nitschke, E. F. Stange and D. Ludwig, “Enhanced Human β-Defensin-2 (hBD-2) Expression by Corticosteroids Is Independent of NF-κB in Colonic Epithelial Cells (CaCo2),” Digestive Diseases and Sciences, Vol. 50, No. 7, 2005, pp. 12521259.
M. H. Giaffer, G. North and C. D. Holdsworth, “Controlled Trial of Polymeric versus Elemental Diet in Treatment of Active Crohn’s Disease,” Lancet, Vol. 335, No. 8693, 1990, pp. 816-819. doi:10.1016/0140-6736(90)90936-Y
H. Sherman, N. Chapnik and O. Froy, “Albumin and Amino Acids Upregulate the Expression of Human BetaDefensin 1,” Molecular Immunology, Vol. 43, No. 10, 2006, pp. 1617-1623. doi:10.1016/j.molimm.2005.09.013