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Inhibition of Nuclear Factor-B in T Cells Suppresses Lung Fibrosis

Departments of ¹ Pulmonary and Critical Care Medicine, ² Immunology and Allergy, ³ Diabetes and Endocrinology, and ⁴ Molecular Pathobiology, Mie University Graduate School of Medicine, Tsu City, Japan; ⁵ Celgene Signal Research Division, San Diego, California; and ⁶ Mie Central Hospital, Tsu City, Japan

Correspondence and requests for reprints should be addressed to Dr. Corina N. D'Alessandro-Gabazza, Department of Pulmonary and Critical Care Medicine, Mie University Graduate School of Medicine, Edobashi 2-174, Tsu City, Mie, Japan 514-8507. E-mail: gabazza{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 (NF)-B and activator protein (AP)-1 are involved in the expression of cytokines from T cells during lung injury.

Objectives: We assessed the potential therapeutic effect of SP100030, a specific inhibitor of T-cell NF-B and AP-1 in lung fibrosis.

Methods: The effect of SP100030 was evaluated using a mouse model of chronic lung fibrosis.

Measurements and Main Results: Mice treated with SP100030, as compared with untreated mice, had significantly less cachexia and less lung injury and had 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 acute and chronic phases of lung fibrosis. SP100030 inhibited the activation of the protein kinase C-isoform in T-cell lines and suppressed NF-B–driven cytokine expression in CD4⁺ and CD8⁺ T cells.

Conclusions: These results suggest that the specific inhibition of NF-B could be useful for the treatment of lung fibrosis.

Key Words: fibrosis • transcription factor • T cells

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject The role of T cells in pulmonary fibrosis is uncertain. Prior studies suggested that inhibiting nuclear factor-B in T cells might help some immune diseases, but the effect on lung fibrosis is unknown. What This Study Adds to the Field This study suggests that T cells are important in pulmonary fibrosis because specific inhibition of the transcription factors NF-B and AP-1 in T cells blocked the development of bleomycin-induced pulmonary fibrosis in mice.

 

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