Involvement of autotaxin/lysophospholipase D expression in intestinal vessels in aggravation of intestinal damage through lymphocyte migration

Hozumi, Hideaki; Hokari, Ryota; Kurihara, Chie; Narimatsu, Kazuyuki; Sato, Hírokazu; Sato, Shingo; Ueda, Toshihide; Higashiyama, Masaaki; Okada, Yoshikiyo; Watanabe, Chikako; Komoto, Shunsuke; Tomita, Kengo; Kawaguchi, Atsushı; Nagao, Shigeaki; Miura, Soichiro

doi:10.1038/labinvest.2013.45

Cited by 42 publications

(54 citation statements)

References 27 publications

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“…Consistent with the expression of autotaxin in the inflamed intestinal mucosa of IBD patients and the involvement of the autotaxin-LPA pathway in pathologic lymphocyte migration in animal models of colitis (Hozumi et al, 2013), we have demonstrated a significant dose-dependent inhibition of the disease activity score by compound-1in the DSS-induced model of IBD. The inhibitor also resulted in a partial reversal of colon-length shortening observed in the model.…”

Section: Discussionsupporting

confidence: 86%

“…Autotaxin expression is significantly higher in the actively inflamed mucosa compared with the quiescent mucosa in the same patient (Hozumi et al, 2013). In addition, autotaxin in the vascular endothelium has been shown to be involved in pathologic lymphocyte migration to the inflamed mucosa in two murine models of colitis, namely the CD4 1 CD25 -T-cell transfer model and the dextran sodium sulfate (DSS)-induced colitis model (Hozumi et al, 2013). Pharmacological intervention with bithionol, a weak inhibitor of autotaxin, has been shown to decrease lymphocyte infiltration and ameliorate colitis in the T-cell transfer model.…”

Section: Introductionmentioning

confidence: 85%

“…Enhanced expression of autotaxin mRNA and aberrant lymphocyte migration have been observed in the inflamed mucosa in patients with Crohn's disease or ulcerative colitis. Autotaxin expression is significantly higher in the actively inflamed mucosa compared with the quiescent mucosa in the same patient (Hozumi et al, 2013). In addition, autotaxin in the vascular endothelium has been shown to be involved in pathologic lymphocyte migration to the inflamed mucosa in two murine models of colitis, namely the CD4 1 CD25 -T-cell transfer model and the dextran sodium sulfate (DSS)-induced colitis model (Hozumi et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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Pharmacological Characterization of a Potent Inhibitor of Autotaxin in Animal Models of Inflammatory Bowel Disease and Multiple Sclerosis

Thirunavukkarasu

Tan

Swearingen

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Autotaxin is a secreted enzyme that catalyzes the conversion of lysophosphatidyl choline into the bioactive lipid mediator lysophosphatidic acid (LPA). It is the primary enzyme responsible for LPA production in plasma. It is upregulated in inflammatory conditions and inhibition of autotaxin may have antiinflammatory activity in a variety of inflammatory diseases. To determine the role of autotaxin and LPA in the pathophysiology of inflammatory disease states, we used a potent and orally bioavailable inhibitor of autotaxin that we have recently identified, and characterized it in mouse models of inflammation, inflammatory bowel disease (IBD), multiple sclerosis (MS), and visceral pain. Compound-1, a potent inhibitor of autotaxin with an IC 50 of ∼2 nM, has good oral pharmacokinetic properties in mice and results in a substantial inhibition of plasma LPA that correlates with drug exposure levels. Treatment with the inhibitor resulted in significant anti-inflammatory and analgesic effects in the carrageenaninduced paw inflammation and acetic acid-induced visceral pain tests, respectively. Compound-1 also significantly inhibited disease activity score in the dextran sodium sulfate-induced model of IBD, and in the experimental autoimmune encephalomyelitis model of MS. In conclusion, the present study demonstrates the anti-inflammatory and analgesic properties of a novel inhibitor of autotaxin that may serve as a therapeutic option for IBD, MS, and pain associated with inflammatory states.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

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Pharmacological Characterization of a Potent Inhibitor of Autotaxin in Animal Models of Inflammatory Bowel Disease and Multiple Sclerosis

Thirunavukkarasu

Tan

Swearingen

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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“…Metabolism and adipogenesis studies in mice indicate that ATX and its product, LPA, participate in energy homeostasis and obesity control ( 56-59, 104, 124, 125 ), which when dysregulated can lead to infl ammation and cancerogenesis. In addition to data showing association of ATX activity with rheumatoid arthritis ( 134 ), liver infl ammation ( 135,136 ), fi brosis development (137)(138)(139)(140)(141), and infl ammatory bowel disease ( 142 ), it has been proposed that ATX is mechanistically involved in linking both hepatitis C to hepatocellular carcinoma ( 143 ) and Epstein-Barr virus positivity to anaplastic large-cell and Hodgkin lymphoma development ( 107 ). MMTV-driven transgenic overexpression of either ATX or each of the three major LPA receptors (LPA1, -2, and -3) causes late-onset, invasive, and metastatic breast cancer development in mammary glands of mice ( 144 ).…”

Section: Role In Physiology and Cancer Pathophysiologymentioning

confidence: 99%

Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease Autotaxin, a lysophospholipase D with pleomorphic effects in oncogenesis and cancer progression

Federico

Jeong

Vellano

et al. 2016

Journal of Lipid Research

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a 125 kDa glycoprotein composed of 915 amino acids ( 1 ). Because it promoted chemotaxis on melanoma cells in an autocrine fashion, the protein was aptly named auto-taxin. Four years after the discovery of the fi rst variant, now commonly referred to as ATX ␣ , or melanoma ATX, a second isoform was cloned by the same team from the teratocarcinoma cell line, Ntera2D1. This polypeptide shared 94% identity with the melanoma protein and was immediately recognized as the alternatively spliced product of the same gene ( 2 ).The initial characterization of the fi rst isoform revealed that ATX biological activity was sensitive to pertussis toxin treatment. Furthermore, not only did the polypeptide share close homology with the murine pyrophosphatase/ type I phosphodiesterase (PDE) PC-1, including a threonine residue crucial for PDE enzymatic activity, but it was also able to hydrolyze PDE substrates in vitro ( 3 ). The confi rmation that ATX was an enzyme came when a new PDE, the PDE1/nucleotide pyrophosphatase (PD-1 ␣ /PDNP 2), was cloned from a cDNA library of human retina and found to be identical to the sequence of melanoma ATX ␣ with the exception of a missing stretch of 52 amino acids encoded by exon 12 in the central region of the open reading frame. The transcript of this variant, now frequently referred to as ATX ␤ , or teratoma ATX, produced a 863 amino acid polypeptide chain with a mass of 99,034 Da ( 4 ), and was independently isolated a few years later in mouse tissues ( 5 ). The third ATX isoform was detected for the fi rst time in rat brain, but was originally designated as PD-I ␣ , a brain-specifi c PDE I/nucleotide pyrophosphatase ( 6 ). Further research showed that PD-I ␣ was identical to ATX ␤ teratoma protein, except for the presence of an additional stretch of 25 amino acids encoded by an alternatively Abstract The ectonucleotide pyrophosphatase/phosphodiesterase type 2, more commonly known as autotaxin (ATX), is an ecto-lysophospholipase D encoded by the human ENNP2 gene. ATX is expressed in multiple tissues and participates in numerous key physiologic and pathologic processes, including neural development, obesity, infl ammation, and oncogenesis, through the generation of the bioactive lipid, lysophosphatidic acid. Overwhelming evidence indicates that altered ATX activity leads to oncogenesis and cancer progression through the modulation of multiple hallmarks of cancer pathobiology. Here, we review the structural and catalytic characteristics of the ectoenzyme, how its expression and maturation processes are regulated, and how the systemic integration of its pleomorphic effects on cells and tissues may contribute to cancer initiation, progression, and therapy. Additionally, the up-to-date spectrum of the most frequent ATX genomic alterations from The Cancer Genome Atlas project is reported for a subset of cancers. ( Fig. 1 ). In 1992, the fi rst alternatively spliced isoform was cloned from the melanoma cell line, A2058, and characterized as STRUCTURE AND ENZYMATIC ACTIVITY ATX belongs to the nuc...

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“…ATX is produced in response to infl ammation to mediate wound repair. If the infl ammation is not resolved, then high ATX concentrations persist in association with infl ammatory diseases such as arthritis and infl ammatory bowel disease ( 1,7,8 ). In addition, infl ammatory bowel disease and hepatitis can progress to carcinogenesis in these organs ( 1 ).…”

mentioning

confidence: 99%

Regulation of autotaxin expression and secretion by lysophosphatidate and sphingosine 1-phosphate

Benesch

Zhao

Curtis

et al. 2015

Journal of Lipid Research

105

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This article is available online at http://www.jlr.org Autotaxin (ATX) is a secreted enzyme, which converts extracellular lysophosphatidylcholine (LPC) into lysophosphatidate (LPA). This is an important reaction in cell signaling because LPA activates at least six G proteincoupled receptors to increase cell division, survival, and migration ( 1, 2 ). ATX serves an essential function in embryonic development because ATX knockout mice die in utero at day 9.5 with defects in vasculogenesis and the development of the neural crest ( 3-6 ). In the postnatal organism, the major function of ATX appears to be in wound healing. ATX is produced in response to infl ammation to mediate wound repair. If the infl ammation is not resolved, then high ATX concentrations persist in association with infl ammatory diseases such as arthritis and infl ammatory bowel disease ( 1,7,8 ). In addition, infl ammatory bowel disease and hepatitis can progress to carcinogenesis in these organs ( 1 ). Signifi cantly, increased ATX activity is associated with the growth of breast tumors ( 9, 10 ) and the ATX gene is among the top 40 most upregulated in metastatic cancer ( 11 ). Blocking LPA production by inhibiting ATX activity with ONO-8430506 decreases the fi rst phase of breast tumor growth and subsequent metastasis by about 60 % in mice ( 9, 12 ). Conversely, increasing the low lipid phosphate phosphatase (LPP)1 activity in cancer cells so as to increase LPA turnover in the tumor and attenuate LPA signaling decreased breast tumor growth and metastasis in mice by about 80% ( 13 ). These studies emphasize the importance of ATX in controlling cell signaling in several physiological and pathological conditions. Consequently, it is important to understand how ATX activity and signaling by LPA are regulated. The present work focuses on the role of ATX and how its expression is controlled.Abstract Autotaxin (ATX) is a secreted enzyme, which produces extracellular lysophosphatidate (LPA) from lysophosphatidylcholine (LPC). LPA activates six G protein-coupled receptors and this is essential for vasculogenesis during embryonic development. ATX is also involved in wound healing and infl ammation, and in tumor growth, metastasis, and chemo-resistance. It is, therefore, important to understand how ATX is regulated. It was proposed that ATX activity is inhibited by its product LPA, or a related lipid called sphingosine 1-phosphate (S1P). We now show that this apparent inhibition is ineffective at the high concentrations of LPC that occur in vivo. Instead, feedback regulation by LPA and S1P is mediated by inhibition of ATX expression resulting from phosphatidylinositol-3-kinase activation. Inhibiting ATX activity in mice with ONO-8430506 severely decreased plasma LPA concentrations and increased ATX mRNA in adipose tissue, which is a major site of ATX production. Consequently, the amount of inhibitor-bound ATX protein in the plasma increased. We, therefore, demonstrate the concept that accumulation of LPA in the circulation decreases ATX production. Howeve...

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Involvement of autotaxin/lysophospholipase D expression in intestinal vessels in aggravation of intestinal damage through lymphocyte migration

Cited by 42 publications

References 27 publications

Pharmacological Characterization of a Potent Inhibitor of Autotaxin in Animal Models of Inflammatory Bowel Disease and Multiple Sclerosis

Pharmacological Characterization of a Potent Inhibitor of Autotaxin in Animal Models of Inflammatory Bowel Disease and Multiple Sclerosis

Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease Autotaxin, a lysophospholipase D with pleomorphic effects in oncogenesis and cancer progression

Regulation of autotaxin expression and secretion by lysophosphatidate and sphingosine 1-phosphate

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