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)

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.

Intragastrically Administered Lysophosphatidic Acids Protect Against Gastric Ulcer in Rats Under Water-Immersion Restraint Stress

“…Previous studies showed that LPA aggravated gastric adenocarcinoma by inducing migration of gastric cancer cells [36] and up-regulating the urokinase-type plasminogen activator receptor in human gastric cancer cells [37]. Interestingly, submucosal connective tissue-type mast cells in the human stomach were shown to release lysophospholipase D due to autotaxin, suggesting its contribution to locally high concentrations of LPA in gastric mucosal tissues [38]. Further work is needed to evaluate the balance between the gastric mucosal-protecting and gastric tumor-aggravating effects of LPA in gastric lumen, as well as the effects of LPA produced locally in gastric submucosal tissues by mast cells under various physiological and pathophysiological conditions.…”

Immunohistochemical Detection of Autotaxin (ATX)/Lysophospholipase D (lysoPLD) in Submucosal Invasive Colorectal Cancer

“…The antibodies against ATX/lysoPLD were used at a dilution of 1:50. The method of immunohistochemical staining was described previously [23]. Because Mori et al reported that a large number of positive cells were detected in the mesenchymal area in the submucosal layer, we counted ATX/ lysoPLD-positive cells in five different fields of the submucosal layer selected at random, under a microscope (expressed as number per x200 field).…”

“…We have recently found that submucosal mast cells in the gastrointestinal tract highly express ATX/lysoPLD, which might play various roles in the pathophysiology of gastrointestinal diseases [23]. In the present study, we hypothesized that mast cells expressing ATX/lysoPLD may play positive roles in cancer invasion and metastases, and assessed the distribution of ATX/ lysoPLD immunohistochemically using a specific monoclonal antibody.…”

Potentiation of the Transient Receptor Potential Vanilloid 1 Channel Contributes to Pruritogenesis in a Rat Model of Liver Disease

“…On the other hand, autaxin is highly expressed in submucosal mast cells also containing chimase and tryptase (50). Tryptase and other proteases, released during mast cell degranulation, not only serve to cleave many substrates involved in inflammation and wound repair, but also potently activate protease-activated PAR 2 receptors (51).…”