Inhibition of 5-lipoxygenase alleviates graft-versus-host disease

• Published in: The Journal of experimental medicine 2017-11, Vol.214 (11), p.3399-3415
• Main Authors: Rezende, Barbara Maximino, Athayde, Rayssa Maciel, Gonçalves, William Antônio, Resende, Carolina Braga, Teles de Tolêdo Bernardes, Priscila, Perez, Denise Alves, Esper, Lísia, Reis, Alesandra Côrte, Rachid, Milene Alvarenga, Castor, Marina Gomes Miranda E, Cunha, Thiago Mattar, Machado, Fabiana Simão, Teixeira, Mauro Martins, Pinho, Vanessa
• Format: Article
• Language: English
• Subjects: Animals; Arachidonate 5-lipoxygenase; Arachidonate 5-Lipoxygenase - genetics; Arachidonate 5-Lipoxygenase - metabolism; Benzopyrans - pharmacology; Carboxylic Acids - pharmacology; Cell Transplantation - adverse effects; Cell Transplantation - methods; Chemokines; Chemokines - metabolism; Chimerism; Cytokines; Cytokines - metabolism; Enzymes; Graft vs Host Disease - drug therapy; Graft vs Host Disease - etiology; Graft vs Host Disease - metabolism; Graft-versus-host reaction; Grafting; Hydroxyurea - analogs & derivatives; Hydroxyurea - pharmacology; Inflammatory diseases; Inhibition; Injury prevention; Intestine; Leukemia; Leukocytes; Leukocytes - cytology; Leukocytes - enzymology; Leukocytes - metabolism; Leukotriene Antagonists - pharmacology; Leukotriene B4; Leukotriene B4 - antagonists & inhibitors; Leukotriene B4 - metabolism; Lipoxygenase; Lipoxygenase Inhibitors - pharmacology; Liver; Mice, Inbred BALB C; Mice, Inbred C57BL; Microscopy, Confocal; Pathogenesis; Pharmacology; Splenocytes; Transplantation, Homologous
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20170261

Leukotriene B (LTB ), 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 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 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 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 axis orchestrates GVHD development and suggest it could be a target for the development of novel therapeutic strategies for GVHD treatment.