OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
OBJECTIVE: We previously implicated the lipid mediator lysophosphatidic acid (LPA) as having a role in dermalfibrosis 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. METHODS: 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. RESULTS: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-6pathways 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. CONCLUSION: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: Sandra M Pasternack; Ivar von Kügelgen; Melanie Müller; Vinzenz Oji; Heiko Traupe; Eli Sprecher; Markus M Nöthen; Andreas R Janecke; Regina C Betz Journal: J Invest Dermatol Date: 2009-06-18 Impact factor: 8.551
Authors: Andrew M Tager; Peter LaCamera; Barry S Shea; Gabriele S Campanella; Moisés Selman; Zhenwen Zhao; Vasiliy Polosukhin; John Wain; Banu A Karimi-Shah; Nancy D Kim; William K Hart; Annie Pardo; Timothy S Blackwell; Yan Xu; Jerold Chun; Andrew D Luster Journal: Nat Med Date: 2007-12-09 Impact factor: 53.440
Authors: Akira Tokumura; Laura D Carbone; Yasuko Yoshioka; Junichi Morishige; Masaki Kikuchi; Arnold Postlethwaite; Mitchell A Watsky Journal: Int J Med Sci Date: 2009-06-05 Impact factor: 3.738
Authors: Daniel Wolff; Vedran Radojcic; Robert Lafyatis; Resat Cinar; Rachel K Rosenstein; Edward W Cowen; Guang-Shing Cheng; Ajay Sheshadri; Anne Bergeron; Kirsten M Williams; Jamie L Todd; Takanori Teshima; Geoffrey D E Cuvelier; Ernst Holler; Shannon R McCurdy; Robert R Jenq; Alan M Hanash; David Jacobsohn; Bianca D Santomasso; Sandeep Jain; Yoko Ogawa; Philipp Steven; Zhonghui Katie Luo; Tina Dietrich-Ntoukas; Daniel Saban; Ervina Bilic; Olaf Penack; Linda M Griffith; Meredith Cowden; Paul J Martin; Hildegard T Greinix; Stefanie Sarantopoulos; Gerard Socie; Bruce R Blazar; Joseph Pidala; Carrie L Kitko; Daniel R Couriel; Corey Cutler; Kirk R Schultz; Steven Z Pavletic; Stephanie J Lee; Sophie Paczesny Journal: Transplant Cell Ther Date: 2021-06-10