Skip to main content

Advertisement

SpringerLink
Log in

Submucosal connective tissue-type mast cells contribute to the production of lysophosphatidic acid (LPA) in the gastrointestinal tract through the secretion of autotaxin (ATX)/lysophospholipase D (lysoPLD)

  • Original Article
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

Lysophosphatidic acid (LPA) is involved in a broad spectrum of biological activities, including wound healing and cancer metastasis. Autotaxin (ATX), originally isolated from a melanoma supernatant as a tumor cell motility-stimulating factor, has been shown to be molecularly identical to lysophospholipase D (lysoPLD), which is the main enzyme in the production of LPA. Although ATX/lysoPLD is known to be widely expressed in normal human tissues, the exact distribution of ATX-producing cells has not been fully investigated. In this study, we evaluated ATX/lysoPLD expression by immunohistochemical staining using a rat anti-ATX mAb in the human gastrointestinal tract and found that submucosal mast cells (MC) highly expressed this enzyme. This was confirmed by immunofluorescent double staining using mAbs to tryptase and chymase. Then, we isolated MC from human gastric tissue by an immunomagnetic method using CD117-microbeads and showed that a subpopulation of CD203c-positive MC showed positive staining for intracellular ATX/lysoPLD on flowcytometry. This was confirmed by Western blotting of the isolated cells. Moreover, a significant level of ATX/lysoPLD release could be detected in the culture supernatants of human MC by Western blot analysis. Our data suggest that submucosal MC play significant roles in various aspects of pathophysiology in the gastrointestinal tract by locally providing bioactive LPA through the production of ATX/lysoPLD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

ATX:

autotaxin

lysoPLD:

lysophospholipase D

LPA:

lysophosphatidic acid

MC:

mast cell

NPP:

ecto-nucleotide pyrophosphatase / phosphodiesterase

References

  1. Aldenborg F, Enerback L (1994) The immunohistochemical demonstration of chymase and tryptase in human intestinal mast cells. Histochem J 267:587–596

    Article  Google Scholar 

  2. An S, Bleu T, Hallmark OG, Goetzl EJ (1998) Characterization of a novel subtype of human G protein-coupled receptor for lysophosphatidic acid. J Biol Chem 27314:7906–7910

    Article  Google Scholar 

  3. Aoki J, Taira A, Takanezawa Y, Kishi Y, Hama K, Kishimoto T, Mizuno K, Saku K, Taguchi R, Arai H (2002) Serum lysophosphatidic acid is produced through diverse phospholipase pathways. J Biol Chem 27750:48737–48744

    Article  Google Scholar 

  4. Bandoh K, Aoki J, Hosono H, Kobayashi S, Kobayashi T, Murakami-Murofushi K, Tsujimoto M, Arai H, Inoue K (1999) Molecular cloning and characterization of a novel human G-protein-coupled receptor, EDG7, for lysophosphatidic acid. J Biol Chem 27439:27776–27785

    Article  Google Scholar 

  5. Baumforth KR, Flavell JR, Reynolds GM, Davies G, Pettitt TR, Wei W, Morgan S, Stankovic T, Kishi Y, Arai H, Nowakova M, Pratt G, Aoki J, Wakelam MJ, Young LS, Murray PG (2005) Induction of autotaxin by the Epstein–Barr virus promotes the growth and survival of Hodgkin’s lymphoma cells. Blood 106(6):2138–2146

    Article  PubMed  CAS  Google Scholar 

  6. Bischoff SC (1996) Mucosal allergy: role of mast cells and eosinophil granulocytes in the gut. Baillieres Clin Gastroenterol 103:443–459

    Article  Google Scholar 

  7. Bischoff SC, Lorentz A, Schwengberg S, Weier G, Raab R, Manns MP (1999) Mast cells are an important cellular source of tumour necrosis factor alpha in human intestinal tissue. Gut 445:643–652

    Article  Google Scholar 

  8. Bischoff SC, Schwengberg S, Wordelmann K, Weimann A, Raab R, Manns MP (1996) Effect of c-kit ligand, stem cell factor, on mediator release by human intestinal mast cells isolated from patients with inflammatory bowel disease and controls. Gut 381:104–114

    Article  Google Scholar 

  9. Bollen M, Gijsbers R, Ceulemans H, Stalmans W, Stefan C (2000) Nucleotide pyrophosphatases/phosphodiesterases on the move. Crit Rev Biochem Mol Biol 356:393–432

    Article  Google Scholar 

  10. Chettibi S, Lawrence AJ, Stevenson RD, Young JD (1994) Effect of lysophosphatidic acid on motility, polarisation and metabolic burst of human neutrophils. FEMS Immunol Med Microbiol 83:271–281

    Article  Google Scholar 

  11. Contos JJ, Fukushima N, Weiner JA, Kaushal D, Chun J (2000) Requirement for the lpA1 lysophosphatidic acid receptor gene in normal suckling behavior. Proc Natl Acad Sci USA 9724:13384–13389

    Article  Google Scholar 

  12. Croset M, Brossard N, Polette A, Lagarde M (2000) Characterization of plasma unsaturated lysophosphatidylcholines in human and rat. Biochem J 345(Pt 1):61–67

    Article  PubMed  CAS  Google Scholar 

  13. Fang X, Yu S, Bast RC, Liu S, Xu HJ, Hu SX, LaPushin R, Claret FX, Aggarwal BB, Lu Y, Mills GB (2004) Mechanisms for lysophosphatidic acid-induced cytokine production in ovarian cancer cells. J Biol Chem 27910:9653–9661

    Article  Google Scholar 

  14. Galli SJ (2000) Mast cells and basophils. Curr Opin Hematol 71:32–39

    Article  Google Scholar 

  15. Galli SJ (1993) New concepts about the mast cell. N Engl J Med 3284:257–265

    Article  Google Scholar 

  16. Gebhardt T, Lorentz A, Detmer F, Trautwein C, Bektas H, Manns MP, Bischoff SC (2005) Growth, phenotype, and function of human intestinal mast cells are tightly regulated by transforming growth factor beta1. Gut 547:928–934

    Article  CAS  Google Scholar 

  17. Ghannadan M, Hauswirth AW, Schernthaner GH, Muller MR, Klepetko W, Schatzl G, Sperr WR, Buhring HJ, Valent P (2002) Detection of novel CD antigens on the surface of human mast cells and basophils. Int Arch Allergy Immunol 1274:299–307

    Article  Google Scholar 

  18. Goding JW, Grobben B, Slegers H (2003) Physiological and pathophysiological functions of the ecto-nucleotide pyrophosphatase/phosphodiesterase family. Biochim Biophys Acta 16381:1–19

    Google Scholar 

  19. Goetzl EJ, An S (1998) Diversity of cellular receptors and functions for the lysophospholipid growth factors lysophosphatidic acid and sphingosine 1-phosphate. FASEB J 1215:1589–1598

    Google Scholar 

  20. Goetzl EJ, Kong Y, Voice JK (2000) Cutting edge: differential constitutive expression of functional receptors for lysophosphatidic acid by human blood lymphocytes. J Immunol 16410:4996–4999

    Google Scholar 

  21. Goldstein SM, Kaempfer CE, Kealey JT, Wintroub BU (1989) Human mast cell carboxypeptidase. Purification and characterization. J Clin Invest 835:1630–1636

    Article  Google Scholar 

  22. Gschwind A, Hart S, Fischer OM, Ullrich A (2003) TACE cleavage of proamphiregulin regulates GPCR-induced proliferation and motility of cancer cells. EMBO J 2210:2411–2421

    Article  Google Scholar 

  23. He SH (2004) Key role of mast cells and their major secretory products in inflammatory bowel disease. World J Gastroenterol 103:309–318

    Google Scholar 

  24. Hecht JH, Weiner JA, Post SR, Chun J (1996) Ventricular zone gene-1 (vzg-1) encodes a lysophosphatidic acid receptor expressed in neurogenic regions of the developing cerebral cortex. J Cell Biol 1354:1071–1083

    Article  Google Scholar 

  25. Hines OJ, Ryder N, Chu J, McFadden D (2000) Lysophosphatidic acid stimulates intestinal restitution via cytoskeletal activation and remodeling. J Surg Res 921:23–28

    Article  CAS  Google Scholar 

  26. Holgate ST (2000) The role of mast cells and basophils in inflammation. Clin Exp Allergy 30(Suppl 1):28–32

    Article  PubMed  Google Scholar 

  27. Irani AM, Bradford TR, Kepley CL, Schechter NM, Schwartz LB (1989) Detection of MCT and MCTC types of human mast cells by immunohistochemistry using new monoclonal anti-tryptase and anti-chymase antibodies. J Histochem Cytochem 3710:1509–1515

    Google Scholar 

  28. Irani AM, Craig SS, DeBlois G, Elson CO, Schechter NM, Schwartz LB (1987) Deficiency of the tryptase-positive, chymase-negative mast cell type in gastrointestinal mucosa of patients with defective T lymphocyte function. J Immunol 13812:4381–4386

    Google Scholar 

  29. Irani AM, Goldstein SM, Wintroub BU, Bradford T, Schwartz LB (1991) Human mast cell carboxypeptidase. Selective localization to MCTC cells. J Immunol 1471:247–253

    Google Scholar 

  30. Johnson RG, Carty SE, Fingerhood BJ, Scarpa A (1980) The internal pH of mast cell granules. FEBS Lett 1201:75–79

    Article  Google Scholar 

  31. Kitayama J, Shida D, Sako A, Ishikawa M, Hama K, Aoki J, Arai H, Nagawa H (2004) Over-expression of lysophosphatidic acid receptor-2 in human invasive ductal carcinoma. Breast Cancer Res 66:R640–R646

    Article  CAS  Google Scholar 

  32. Kondo K, Muramatsu M, Okamoto Y, Jin D, Takai S, Tanigawa N, Miyazaki M (2006) Expression of chymase-positive cells in gastric cancer and its correlation with the angiogenesis. J Surg Oncol 931:36–42; discussion 42–33

    Article  CAS  Google Scholar 

  33. Mekori YA, Metcalfe DD (2000) Mast cells in innate immunity. Immunol Rev 173:131–140

    Article  PubMed  CAS  Google Scholar 

  34. Mills GB, Moolenaar WH (2003) The emerging role of lysophosphatidic acid in cancer. Nat Rev Cancer 38:582–591

    Article  CAS  Google Scholar 

  35. Moolenaar WH (1995) Lysophosphatidic acid, a multifunctional phospholipid messenger. J Biol Chem 27022:12949–12952

    Google Scholar 

  36. Murata J, Lee HY, Clair T, Krutzsch HC, Arestad AA, Sobel ME, Liotta LA, Stracke ML (1994) cDNA cloning of the human tumor motility-stimulating protein, autotaxin, reveals a homology with phosphodiesterases. J Biol Chem 26948:30479–30484

    Google Scholar 

  37. Nam SW, Clair T, Campo CK, Lee HY, Liotta LA, Stracke ML (2000) Autotaxin (ATX), a potent tumor motogen, augments invasive and metastatic potential of ras-transformed cells. Oncogene 192:241–247

    Article  CAS  Google Scholar 

  38. Nam SW, Clair T, Kim YS, McMarlin A, Schiffmann E, Liotta LA, Stracke ML (2001) Autotaxin (NPP-2), a metastasis-enhancing motogen, is an angiogenic factor. Cancer Res 6118:6938–6944

    Google Scholar 

  39. Okayama Y, Hunt TC, Kassel O, Ashman LK, Church MK (1994) Assessment of the anti-c-kit monoclonal antibody YB5.B8 in affinity magnetic enrichment of human lung mast cells. J Immunol Methods 1692:153–161

    Article  Google Scholar 

  40. Palmetshofer A, Robson SC, Nehls V (1999) Lysophosphatidic acid activates nuclear factor kappa B and induces proinflammatory gene expression in endothelial cells. Thromb Haemost 825:1532–1537

    Google Scholar 

  41. Panetti TS, Nowlen J, Mosher DF (2000) Sphingosine-1-phosphate and lysophosphatidic acid stimulate endothelial cell migration. Arterioscler Thromb Vasc Biol 204:1013–1019

    Google Scholar 

  42. Pedotti R, De Voss JJ, Steinman L, Galli SJ (2003) Involvement of both ‘allergic’ and ‘autoimmune’ mechanisms in EAE, MS and other autoimmune diseases. Trends Immunol 249:479–484

    Article  CAS  Google Scholar 

  43. Rahaman M, Costello RW, Belmonte KE, Gendy SS, Walsh MT (2006) Neutrophil sphingosine 1-phosphate and lysophosphatidic acid receptors in pneumonia. Am J Respir Cell Mol Biol 342:233–241

    Article  CAS  Google Scholar 

  44. Ribatti D, Ennas MG, Vacca A, Ferreli F, Nico B, Orru S, Sirigu P (2003) Tumor vascularity and tryptase-positive mast cells correlate with a poor prognosis in melanoma. Eur J Clin Invest 335:420–425

    Article  Google Scholar 

  45. Rizza C, Leitinger N, Yue J, Fischer DJ, Wang DA, Shih PT, Lee H, Tigyi G, Berliner JA (1999) Lysophosphatidic acid as a regulator of endothelial/leukocyte interaction. Lab Invest 7910:1227–1235

    Google Scholar 

  46. Savaskan NE, Rocha L, Kotter MR, Baer A, Lubec G, van Meeteren LA, Kishi Y, Aoki J, Moolenaar WH, Nitsch R, Brauer AU (2007) Autotaxin (NPP-2) in the brain: cell type-specific expression and regulation during development and after neurotrauma. Cell Mol Life Sci 642:230–243

    Article  CAS  Google Scholar 

  47. Segura BJ, Zhang W, Cowles RA, Xiao L, Lin TR, Logsdon C, Mulholland MW (2004) Lysophosphatidic acid stimulates calcium transients in enteric glia. Neuroscience 1233:687–693

    Article  CAS  Google Scholar 

  48. Sengupta S, Wang Z, Tipps R, Xu Y (2004) Biology of LPA in health and disease. Semin Cell Dev Biol 155:503–512

    Article  CAS  Google Scholar 

  49. Shah PM, Husby S, Damsgaard TE, Nielsen HV, Schiotz PO (1998) Purification of human colonic and gastric mast cells. J Immunol Methods 214:141–148

    Article  PubMed  CAS  Google Scholar 

  50. Shida D, Kitayama J, Yamaguchi H, Hama K, Aoki J, Arai H, Yamashita H, Mori K, Sako A, Konishi T, Watanabe T, Sakai T, Suzuki R, Ohta H, Takuwa Y, Nagawa H (2004) Dual mode regulation of migration by lysophosphatidic acid in human gastric cancer cells. Exp Cell Res 3012:168–178

    Article  CAS  Google Scholar 

  51. Shida D, Kitayama J, Yamaguchi H, Okaji Y, Tsuno NH, Watanabe T, Takuwa Y, Nagawa H (2003) Lysophosphatidic acid (LPA) enhances the metastatic potential of human colon carcinoma DLD1 cells through LPA1. Cancer Res 637:1706–1711

    Google Scholar 

  52. Shida D, Watanabe T, Aoki J, Hama K, Kitayama J, Sonoda H, Kishi Y, Yamaguchi H, Sasaki S, Sako A, Konishi T, Arai H, Nagawa H (2004) Aberrant expression of lysophosphatidic acid (LPA) receptors in human colorectal cancer. Lab Invest 8410:1352–1362

    Article  CAS  Google Scholar 

  53. Stassar MJ, Devitt G, Brosius M, Rinnab L, Prang J, Schradin T, Simon J, Petersen S, Kopp-Schneider A, Zoller M (2001) Identification of human renal cell carcinoma associated genes by suppression subtractive hybridization. Br J Cancer 859:1372–1382

    Article  Google Scholar 

  54. Stefan C, Jansen S, Bollen M (2005) NPP-type ectophosphodiesterases: unity in diversity. Trends Biochem Sci 3010:542–550

    Article  CAS  Google Scholar 

  55. Stracke M, Liotta LA, Schiffmann E (1993) The role of autotaxin and other motility stimulating factors in the regulation of tumor cell motility. Symp Soc Exp Biol 47:197–214

    PubMed  CAS  Google Scholar 

  56. Stracke ML, Clair T, Liotta LA (1997) Autotaxin, tumor motility-stimulating exophosphodiesterase. Adv Enzyme Regul 37:135–144

    Article  PubMed  CAS  Google Scholar 

  57. Stracke ML, Krutzsch HC, Unsworth EJ, Arestad A, Cioce V, Schiffmann E, Liotta LA (1992) Identification, purification, and partial sequence analysis of autotaxin, a novel motility-stimulating protein. J Biol Chem 2674:2524–2529

    Google Scholar 

  58. Sturm A, Sudermann T, Schulte KM, Goebell H, Dignass AU (1999) Modulation of intestinal epithelial wound healing in vitro and in vivo by lysophosphatidic acid. Gastroenterology 1172:368–377

    Article  Google Scholar 

  59. Sturm A, Zeeh J, Sudermann T, Rath H, Gerken G, Dignass AU (2002) Lisofylline and lysophospholipids ameliorate experimental colitis in rats. Digestion 661:23–29

    Article  CAS  Google Scholar 

  60. Tanaka M, Kishi Y, Takanezawa Y, Kakehi Y, Aoki J, Arai H (2004) Prostatic acid phosphatase degrades lysophosphatidic acid in seminal plasma. FEBS Lett 571:197–204

    Article  PubMed  CAS  Google Scholar 

  61. Thies F, Delachambre MC, Bentejac M, Lagarde M, Lecerf J (1992) Unsaturated fatty acids esterified in 2-acyl-l-lysophosphatidylcholine bound to albumin are more efficiently taken up by the young rat brain than the unesterified form. J Neurochem 593:1110–1116

    Article  Google Scholar 

  62. Tokumura A, Fujimoto H, Yoshimoto O, Nishioka Y, Miyake M, Fukuzawa K (1999) Production of lysophosphatidic acid by lysophospholipase D in incubated plasma of spontaneously hypertensive rats and Wistar Kyoto rats. Life Sci 653:245–253

    Article  Google Scholar 

  63. Tokumura A, Majima E, Kariya Y, Tominaga K, Kogure K, Yasuda K, Fukuzawa K (2002) Identification of human plasma lysophospholipase D, a lysophosphatidic acid-producing enzyme, as autotaxin, a multifunctional phosphodiesterase. J Biol Chem 27742:39436–39442

    Article  CAS  Google Scholar 

  64. Tokumura A, Tominaga K, Yasuda K, Kanzaki H, Kogure K, Fukuzawa K (2002) Lack of significant differences in the corrected activity of lysophospholipase D, producer of phospholipid mediator lysophosphatidic acid, in incubated serum from women with and without ovarian tumors. Cancer 941:141–151

    Article  CAS  Google Scholar 

  65. Tomita M, Matsuzaki Y, Edagawa M, Shimizu T, Hara M, Sekiya R, Onitsuka T (2001) Association of mast cells with tumor angiogenesis in esophageal squamous cell carcinoma. Dis Esophagus 142:135–138

    Article  Google Scholar 

  66. Umezu-Goto M, Kishi Y, Taira A, Hama K, Dohmae N, Takio K, Yamori T, Mills GB, Inoue K, Aoki J, Arai H (2002) Autotaxin has lysophospholipase D activity leading to tumor cell growth and motility by lysophosphatidic acid production. J Cell Biol 1582:227–233

    Article  CAS  Google Scholar 

  67. Umezu-Goto M, Tanyi J, Lahad J, Liu S, Yu S, Lapushin R, Hasegawa Y, Lu Y, Trost R, Bevers T, Jonasch E, Aldape K, Liu J, James RD, Ferguson CG, Xu Y, Prestwich GD, Mills GB (2004) Lysophosphatidic acid production and action: validated targets in cancer? J Cell Biochem 926:1115–1140

    Article  CAS  Google Scholar 

  68. von Boyen GB, Steinkamp M, Reinshagen M, Schafer KH, Adler G, Kirsch J (2004) Proinflammatory cytokines increase glial fibrillary acidic protein expression in enteric glia. Gut 532:222–228

    Article  Google Scholar 

  69. Walls AF, Jones DB, Williams JH, Church MK, Holgate ST (1990) Immunohistochemical identification of mast cells in formaldehyde-fixed tissue using monoclonal antibodies specific for tryptase. J Pathol 1622:119–126

    Article  Google Scholar 

  70. Yang SY, Lee J, Park CG, Kim S, Hong S, Chung HC, Min SK, Han JW, Lee HW, Lee HY (2002) Expression of autotaxin (NPP-2) is closely linked to invasiveness of breast cancer cells. Clin Exp Metastasis 197:603–608

    Article  Google Scholar 

  71. Yang Y, Mou L, Liu N, Tsao MS (1999) Autotaxin expression in non-small-cell lung cancer. Am J Respir Cell Mol Biol 212:216–222

    Google Scholar 

  72. Zhang G, Zhao Z, Xu S, Ni L, Wang X (1999) Expression of autotaxin mRNA in human hepatocellular carcinoma. Chin Med J (Engl) 1124:330–332

    Google Scholar 

  73. Zheng Y, Voice JK, Kong Y, Goetzl EJ (2000) Altered expression and functional profile of lysophosphatidic acid receptors in mitogen-activated human blood T lymphocytes. FASEB J 1415:2387–2389

    Google Scholar 

Download references

Acknowledgements

This work was supported partly by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and partly by a grant from the Ministry of Health, Labor and Welfare of Japan. We thank Dr. M. Uchikawa for his kind help to conjugate FITC to anti-ATX mAb, and Ms. C. Uchikawa and Ms. K. Amitani for their excellent technical assistance.

Author information

Authors and Affiliations

  1. Department of Surgical Oncology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Ken Mori, Joji Kitayama, Dai Shida, Hiroharu Yamashita & Hirokazu Nagawa

  2. Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan

    Junken Aoki, Yasuhiro Kishi & Hiroyuki Arai

Authors
  1. Ken Mori
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joji Kitayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Junken Aoki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yasuhiro Kishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dai Shida
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hiroharu Yamashita
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hiroyuki Arai
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hirokazu Nagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ken Mori.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mori, K., Kitayama, J., Aoki, J. et al. Submucosal connective tissue-type mast cells contribute to the production of lysophosphatidic acid (LPA) in the gastrointestinal tract through the secretion of autotaxin (ATX)/lysophospholipase D (lysoPLD). Virchows Arch 451, 47–56 (2007). https://doi.org/10.1007/s00428-007-0425-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-007-0425-4

Keywords

Search

Navigation