IL-1β and TLR4 signaling are involved in the aggravated murine acute graft-versus-host disease caused by delayed bortezomib administration.

Abstract

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-1β was critically involved, and the subsequent aGVHD could be alleviated by IL-1β blockade. Bortezomib treatment after dendritic cell (DC) activation resulted in drastically elevated IL-1β production, whereas bortezomib treatment before DC activation inhibited IL-1β production, suggesting that the timing of bortezomib administration significantly affected IL-1β 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-1β 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-1β.

• Authors: Yong Liang, Shoubao Ma, Yanming Zhang, Ying Wang, Qiao Cheng, Yan Wu, Yue Jin, Donghui Zheng, Depei Wu, Haiyan Liu
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 192 Issue 3 Pg. 1277-85 (Feb 01 2014) ISSN: 1550-6606 [Electronic] United States
• PMID: 24363427 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Boronic Acids
• Cytokines
• Interleukin 1 Receptor Antagonist Protein
• Interleukin-1beta
• Lipopolysaccharides
• Protease Inhibitors
• Pyrazines
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• Bortezomib
• Cyclophosphamide

Topics

• Acute Disease
• Animals
• Bone Marrow Transplantation
• Boronic Acids (administration & dosage, pharmacology, toxicity)
• Bortezomib
• Cell Transplantation
• Cyclophosphamide (administration & dosage)
• Cytokines (biosynthesis, genetics)
• Dendritic Cells (drug effects, immunology, metabolism)
• Gene Expression Regulation (drug effects)
• Graft vs Host Disease (chemically induced, pathology)
• Interleukin 1 Receptor Antagonist Protein (pharmacology)
• Interleukin-1beta (antagonists & inhibitors, biosynthesis, genetics, physiology)
• Lipopolysaccharides (toxicity)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Protease Inhibitors (administration & dosage, pharmacology, toxicity)
• Pyrazines (administration & dosage, pharmacology, toxicity)
• Signal Transduction (physiology)
• Specific Pathogen-Free Organisms
• Spleen (cytology)
• Toll-Like Receptor 4 (physiology)
• Transplantation Conditioning (methods)
• Whole-Body Irradiation