| First Author | Liang Y | Year | 2014 |
| Journal | J Immunol | Volume | 192 |
| Issue | 3 | Pages | 1277-85 |
| PubMed ID | 24363427 | Mgi Jnum | J:207316 |
| Mgi Id | MGI:5555999 | Doi | 10.4049/jimmunol.1203428 |
| Citation | Liang Y, et al. (2014) IL-1beta and TLR4 signaling are involved in the aggravated murine acute graft-versus-host disease caused by delayed bortezomib administration. J Immunol 192(3):1277-85 |
| abstractText | It was shown that the proteasome inhibitor, bortezomib, administered immediately following allogeneic bone marrow transplantation resulted in marked inhibition of acute graft-versus-host disease (aGVHD), with retention of graft-versus-tumor effects. However, continuous bortezomib administration resulted in significant acceleration of graft-versus-host disease-dependent morbidity. We carried out studies to dissect the mechanisms of aggravated aGVHD caused by delayed bortezomib administration. First, we demonstrated that IL-1beta was critically involved, and the subsequent aGVHD could be alleviated by IL-1beta blockade. Bortezomib treatment after dendritic cell (DC) activation resulted in drastically elevated IL-1beta production, whereas bortezomib treatment before DC activation inhibited IL-1beta production, suggesting that the timing of bortezomib administration significantly affected IL-1beta production by DCs. We further demonstrated that delayed administration of bortezomib accelerated aGVHD through TLR4 signaling. Because the LPS levels were much lower with reduced-intensity conditioning compared with high-dose irradiation, the accelerated graft-versus-host disease-dependent morbidity with delayed bortezomib administration could be rescued by reduced-intensity conditioning. Our studies suggested that TLR4 pathway activation and delayed bortezomib administration amplified the production of IL-1beta and other inflammatory cytokines, which resulted in accelerated aGVHD-dependent morbidity. These results indicated that decreased toxicity of continuous bortezomib administration could be achieved by reduced-intensity conditioning or by inhibiting IL-1beta. |
