title: Involvement of autotaxin/lysophospholipase D expression in intestinal vessels in aggravation of intestinal damage through lymphocyte migration.
abstract: Lysophosphatidic acid (LPA) has a critical role in lymphocyte migration to secondary lymphoid organs. Autotaxin (ATX)/lysophospholipase D, in the vascular endothelium, is the main enzyme involved in LPA production. Whether ATX is involved in pathological lymphocyte migration to the inflamed mucosa has not been studied. We investigated the involvement of ATX in inflammatory bowel disease patients and two murine models of colitis. Tissue samples were obtained by intestinal biopsies from patients with Crohn's disease and those with ulcerative colitis with informed consent. ATX immunoreactivity was colocalized with MAdCAM-1-positive high-endothelial-like vessels, close to sites of lymphocyte infiltration. Enhanced expression of ATX mRNA was observed in the inflamed mucosa from Crohn's disease and ulcerative colitis patients. ATX mRNA expression level was remarkably higher in the actively inflamed mucosa than in the quiescent mucosa in the same patient. In the T-cell-transferred mouse model, ATX mRNA expression level gradually increased as colitis developed. In the dextran sodium sulfate mouse model, the expression level was considerably higher in colonic mucosa of chronically developed colitis than in colonic mucosa of acute colitis. Administration of an ATX inhibitor, bithionol, remarkably decreased lymphocyte migration to the intestine and ameliorated both dextran sodium sulfate-induced colitis and CD4-induced ileocolitis. In transwell assays, administration of bithionol or 1-bromo-3(s)-hydroxy-4-(palmitoyloxy) butylphosphonate (BrP-LPA) significantly decreased transmigration of splenocytes through high-endothelial-like vessels induced by TNF-α. We conclude that enhanced expression of ATX in the active mucosa has been implicated in the pathophysiology of inflammatory bowel disease through enhancing aberrant lymphocyte migration to the inflamed mucosa.
authors.affiliation: Internal Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Hozumi
authors.forename: Ryota
authors.initials: R
authors.lastname: Hokari
authors.forename: Chie
authors.initials: C
authors.lastname: Kurihara
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Narimatsu
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Sato
authors.forename: Shingo
authors.initials: S
authors.lastname: Sato
authors.forename: Toshihide
authors.initials: T
authors.lastname: Ueda
authors.forename: Masaaki
authors.initials: M
authors.lastname: Higashiyama
authors.forename: Yoshikiyo
authors.initials: Y
authors.lastname: Okada
authors.forename: Chikako
authors.initials: C
authors.lastname: Watanabe
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Komoto
authors.forename: Kengo
authors.initials: K
authors.lastname: Tomita
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kawaguchi
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Nagao
authors.forename: Soichiro
authors.initials: S
authors.lastname: Miura
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001735:Bithionol; D015704:CD4 Antigens; D002465:Cell Movement; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D003093:Colitis, Ulcerative / Q000378:metabolism* / Q000473:pathology; D003106:Colon / Q000378:metabolism / Q000473:pathology; D003424:Crohn Disease / Q000378:metabolism* / Q000473:pathology; D016264:Dextran Sulfate; D005260:Female; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit; D007413:Intestinal Mucosa / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D008214:Lymphocytes; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D010727:Phosphoric Diester Hydrolases / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D000099189:Lysophospholipase D
chemical_list: D001735:Bithionol; D015704:CD4 Antigens; D016264:Dextran Sulfate; D053645:Interleukin-2 Receptor alpha Subunit; D010727:Phosphoric Diester Hydrolases; D000099189:Lysophospholipase D