title: An Autotaxin/Lysophosphatidic Acid/Interleukin-6 Amplification Loop Drives Scleroderma Fibrosis.
abstract: We previously implicated the lipid mediator lysophosphatidic acid (LPA) as having a role in dermal fibrosis in systemic sclerosis (SSc). The aim of this study was to identify the role of the LPA-producing enzyme autotaxin (ATX), and to connect the ATX/LPA and interleukin-6 (IL-6) pathways in SSc.
  
  
  
  We evaluated the effect of a novel ATX inhibitor, PAT-048, on fibrosis and IL-6 expression in the mouse model of bleomycin-induced dermal fibrosis. We used dermal fibroblasts from SSc patients and control subjects to evaluate LPA-induced expression of IL-6, and IL-6-induced expression of ATX. We next evaluated whether LPA-induced ATX expression is dependent on IL-6, and whether baseline IL-6 expression in fibroblasts from SSc patients is dependent on ATX. Finally, we compared ATX and IL-6 expression in the skin of patients with SSc and healthy control subjects.
  
  
  
  PAT-048 markedly attenuated bleomycin-induced dermal fibrosis when treatment was initiated before or after the development of fibrosis. LPA stimulated expression of IL-6 in human dermal fibroblasts, and IL-6 stimulated fibroblast expression of ATX, connecting the ATX/LPA and IL-6 pathways in an amplification loop. IL-6 knockdown abrogated LPA-induced ATX expression in fibroblasts, and ATX inhibition attenuated IL-6 expression in fibroblasts and the skin of bleomycin-challenged mice. Expression of both ATX and IL-6 was increased in SSc skin, and LPA-induced IL-6 levels and IL-6-induced ATX levels were increased in fibroblasts from SSc patients compared with controls.
  
  
  
  ATX is required for the development and maintenance of dermal fibrosis in a mouse model of bleomycin-induced SSc and enables 2 major mediators of SSc fibrogenesis, LPA and IL-6, to amplify the production of each other. Our results suggest that concurrent inhibition of these 2 pathways may be an effective therapeutic strategy for dermal fibrosis in SSc.
authors.affiliation: Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Flavia V
authors.initials: FV
authors.lastname: Castelino
authors.affiliation: PharmAkea, San Diego, California.
authors.forename: Gretchen
authors.initials: G
authors.lastname: Bain
authors.affiliation: Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Veronica A
authors.initials: VA
authors.lastname: Pace
authors.affiliation: Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Katharine E
authors.initials: KE
authors.lastname: Black
authors.affiliation: Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Leaya
authors.initials: L
authors.lastname: George
authors.affiliation: Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Clemens K
authors.initials: CK
authors.lastname: Probst
authors.affiliation: PharmAkea, San Diego, California.
authors.forename: Lance
authors.initials: L
authors.lastname: Goulet
authors.affiliation: Boston University, Boston, Massachusetts.
authors.forename: Robert
authors.initials: R
authors.lastname: Lafyatis
authors.affiliation: Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Tager
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D001761:Bleomycin / Q000633:toxicity; D016022:Case-Control Studies; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005355:Fibrosis; D006801:Humans; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000378:metabolism*; D008246:Lysophospholipids / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects / Q000378:metabolism*; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D012595:Scleroderma, Systemic / Q000378:metabolism* / Q000473:pathology; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D000099189:Lysophospholipase D
chemical_list: D001565:Benzoates; D001761:Bleomycin; D015850:Interleukin-6; D008246:Lysophospholipids; D010726:Phosphodiesterase Inhibitors; D010727:Phosphoric Diester Hydrolases; D034741:RNA, Small Interfering; D000099189:Lysophospholipase D; C508600:IL6 protein, human; C000621188:PAT-048; C577686:interleukin-6, mouse; C032881:lysophosphatidic acid