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Inhibition of 5-lipoxygenase alleviates graft-versus-host disease.
- Source :
-
The Journal of experimental medicine [J Exp Med] 2017 Nov 06; Vol. 214 (11), pp. 3399-3415. Date of Electronic Publication: 2017 Sep 25. - Publication Year :
- 2017
-
Abstract
- Leukotriene B <subscript>4</subscript> (LTB <subscript>4</subscript> ), a proinflammatory mediator produced by the enzyme 5-lipoxygenase (5-LO), is associated with the development of many inflammatory diseases. In this study, we evaluated the participation of the 5-LO/LTB <subscript>4</subscript> axis in graft-versus-host disease (GVHD) pathogenesis by transplanting 5-LO-deficient leukocytes and investigated the effect of pharmacologic 5-LO inhibition by zileuton and LTB <subscript>4</subscript> inhibition by CP-105,696. Mice that received allogeneic transplant showed an increase in nuclear 5-LO expression in splenocytes, indicating enzyme activation after GVHD. Mice receiving 5-LO-deficient cell transplant or zileuton treatment had prolonged survival, reduced GVHD clinical scores, reduced intestinal and liver injury, and decreased levels of serum and hepatic LTB <subscript>4</subscript> These results were associated with inhibition of leukocyte recruitment and decreased production of cytokines and chemokines. Treatment with CP-105,696 achieved similar effects. The chimerism or the beneficial graft-versus-leukemia response remained unaffected. Our data provide evidence that the 5-LO/LTB <subscript>4</subscript> axis orchestrates GVHD development and suggest it could be a target for the development of novel therapeutic strategies for GVHD treatment.<br /> (© 2017 Rezende et al.)
- Subjects :
- Animals
Arachidonate 5-Lipoxygenase genetics
Benzopyrans pharmacology
Carboxylic Acids pharmacology
Cell Transplantation adverse effects
Chemokines metabolism
Cytokines metabolism
Graft vs Host Disease drug therapy
Graft vs Host Disease etiology
Hydroxyurea analogs & derivatives
Hydroxyurea pharmacology
Leukocytes cytology
Leukocytes enzymology
Leukocytes metabolism
Leukotriene Antagonists pharmacology
Leukotriene B4 antagonists & inhibitors
Lipoxygenase Inhibitors pharmacology
Mice, Inbred BALB C
Mice, Inbred C57BL
Microscopy, Confocal
Transplantation, Homologous
Arachidonate 5-Lipoxygenase metabolism
Cell Transplantation methods
Graft vs Host Disease metabolism
Leukotriene B4 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1540-9538
- Volume :
- 214
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- The Journal of experimental medicine
- Publication Type :
- Academic Journal
- Accession number :
- 28947611
- Full Text :
- https://doi.org/10.1084/jem.20170261