Submitted on September 11, 2006
Accepted on September 21, 2007
Inhibition of Nuclear Factor-
B in T cells Suppresses Lung Fibrosis
Hajime Fujimoto1, Corina N D'Alessandro-Gabazza1*, Moorthy SS Palanki2, Paul E Erdman2, Takehiro Takagi1, Esteban C Gabazza3, Nelson E Bruno4, Yutaka Yano4, Tatsuya Hayashi5, Shigenori Tamaki6, Yasuhiro Sumida4, Yukihiko Adachi1, Koji Suzuki5, and Osamu Taguchi1
1 Department of Pulmonary and Critical Care Medicine, Mie University Graduate School of Medicine, Tsu city, Mie, Japan,
2 Department of Immunology, Mie University Graduate School of Medicine, Tsu city, Mie, Japan,
3 Department of Pulmonary and Critical Care Medicine, Mie University Graduate School of Medicine, Tsu city, Mie, Japan; Department of Immunology, Mie University Graduate School of Medicine, Tsu city, Mie, Japan,
4 Department of Diabetes and Endocrinology, Mie University Graduate School of Medicine, Tsu city, Mie, Japan,
5 Department of Molecular Pathobiology, Mie University Graduate School of Medicine, Tsu city, Mie, Japan,
6 Celgene Signal Research Division, San Diego, CA, USA
* To whom correspondence should be addressed. E-mail: dalessac{at}clin.medic.mie-u.ac.jp.
Rationale: Cytokines secreted by T cells play a pivotal role in the pathogenesis of lung injury and fibrosis, and the transcription factors nuclear factor-
B and activator protein-1 are involved in the expression of cytokines from T cells during lung injury. Objectives & methods: We assessed the potential therapeutic effect of SP100030, a specific inhibitor of T cell nuclear factor-B and activator protein-1, by using a mouse model of chronic lung fibrosis. Results: Mice treated with SP100030, as compared to untreated mice, had significantly less cachexia and less lung injury, as well as decreased levels of inflammatory cytokines and growth factors, decreased activation of coagulation activation, and decreased collagen deposition in the lung. The inhibitory activity of SP100030 was dose-dependent and was effective in both acute and chronic phases of lung fibrosis. SP100030 inhibited the activation of the protein kinase C
-isoform in T cell lines, and suppressed nuclear factor-B -driven cytokine expression in CD4+ and CD8+ T cells. Conclusions: These results suggest that the specific inhibition of nuclear factor-B could be useful for the treatment of lung fibrosis.
Key words: Lung fibrosis, nuclear factor B, T cells
