The natural organosulfur compound dipropyltetrasulfide prevents HOCl-induced systemic sclerosis in the mouse
1 Université Paris Descartes, Faculté de Médecine, EA 1833 et Laboratoire d’Immunologie Biologique, Hôpital Cochin AP-HP, 75679 Paris, cedex 14, France
2 Division of Bioorganic Chemistry, School of Pharmacy, Saarland University, Campus B2.1, D-66123 Saarbrücken, Germany
3 Faculté de Médecine de Reims, Service de Médecine Interne, Maladies Infectieuses, Immunologie Clinique, Hôpital Robert Debré, 51092 Reims, cedex, France
4 Exeter University Medical School, University of Exeter, EX1 2LU Exeter, Devon, UK
5 ECOspray Limited, Grange Farm Hilborough, Thetford IP26 5BT UK
Arthritis Research & Therapy 2013, 15:R167 doi:10.1186/ar4351Published: 28 October 2013
The aim of this study was to test the naturally occurring organosulfur compound dipropyltetrasulfide (DPTTS), found in plants, which has antibiotic and anticancer properties, as a treatment for HOCl-induced systemic sclerosis in the mouse.
The prooxidative, antiproliferative, and cytotoxic effects of DPTTS were evaluated ex vivo on fibroblasts from normal and HOCl mice. In vivo, the antifibrotic and immunomodulating properties of DPTTS were evaluated in the skin and lungs of HOCl mice.
H2O2 production was higher in fibroblasts derived from HOCl mice than in normal fibroblasts (P < 0.05). DPTTS did not increase H2O2 production in normal fibroblasts, but DPTTS dose-dependently increased H2O2 production in HOCl fibroblasts (P < 0.001 with 40 μM DPTTS). Because H2O2 reached a lethal threshold in cells from HOCl mice, the antiproliferative, cytotoxic, and proapoptotic effects of DPTTS were significantly higher in HOCl fibroblasts than for normal fibroblasts. In vivo, DPTTS decreased dermal thickness (P < 0.001), collagen content in skin (P < 0.01) and lungs (P < 0.05), αSMA (P < 0.01) and pSMAD2/3 (P < 0.01) expression in skin, formation of advanced oxidation protein products and anti-DNA topoisomerase-1 antibodies in serum (P < 0.05) versus untreated HOCl mice. Moreover, in HOCl mice, DPTTS reduced splenic B-cell counts (P < 0.01), the proliferative rates of B-splenocytes stimulated by lipopolysaccharide (P < 0.05), and T-splenocytes stimulated by anti-CD3/CD28 mAb (P < 0.001). Ex vivo, it also reduced the production of IL-4 and IL-13 by activated T cells (P < 0.05 in both cases).
The natural organosulfur compound DPTTS prevents skin and lung fibrosis in the mouse through the selective killing of diseased fibroblasts and its immunomodulating properties. DPTTS may be a potential treatment for systemic sclerosis.