Lentivirus expressing soluble ST2 alleviates bleomycin-induced pulmonary fibrosis in mice.

It has been shown that the expression of ST2, a receptor of interleukin (IL)-33, is elevated in the lungs of idiopathic pulmonary fibrosis patients and bleomycin-induced mouse models, however its contribution to the development of pulmonary fibrosis has yet to be tested. In the present study, we treated mice by intranasal instillation of lentivirus expressing soluble ST2 and evaluated lung inflammation and fibrosis in the bleomycin-induced pulmonary fibrosis mouse model. We found that ST2 lentivirus treatment significantly improved survival rate and reduced weight loss compared with controls treated with empty lentivirus. Furthermore, ST2 treatment profoundly attenuated the pulmonary inflammatory cell infiltration and fibrotic changes. Finally, ST2 treatment markedly lowered the levels of IL-4, IL-6, IL-13, IL-33, monocyte chemoattractant protein-1, and transforming growth factor-ß1, whereas it increased the levels of interferon-γ in bronchoalveolar lavage fluid. The results indicate that ST2 might prevent bleomycin-induced pulmonary fibrosis possibly through downregulating proinflammatory and profibrotic mediators. This study suggests that lentivirus expressing soluble ST2 might represent an effective therapeutic approach in the treatment of pulmonary fibrotic diseases.

The interleukin (IL)-1 cytokine family--Balance between agonists and antagonists in inflammatory diseases.

The interleukin (IL)-1 family of cytokines comprises 11 members, including 7 pro-inflammatory agonists (IL-1α, IL-1ß, IL-18, IL-33, IL-36α, IL-36ß, IL-36γ) and 4 defined or putative antagonists (IL-1R antagonist (IL-1Ra), IL-36Ra, IL-37, and IL-38) exerting anti-inflammatory activities. Except for IL-1Ra, IL-1 cytokines do not possess a leader sequence and are secreted via an unconventional pathway. In addition, IL-1ß and IL-18 are produced as biologically inert pro-peptides that require cleavage by caspase-1 in their N-terminal region to generate active proteins. N-terminal processing is also required for full activity of IL-36 cytokines. The IL-1 receptor (IL-1R) family comprises 10 members and includes cytokine-specific receptors, co-receptors and inhibitory receptors. The signaling IL-1Rs share a common structure with three extracellular immunoglobulin (Ig) domains and an intracellular Toll-like/IL-1R (TIR) domain. IL-1 cytokines bind to their specific receptor, which leads to the recruitment of a co-receptor and intracellular signaling. IL-1 cytokines induce potent inflammatory responses and their activity is tightly controlled at the level of production, protein processing and maturation, receptor binding and post-receptor signaling by naturally occurring inhibitors. Some of these inhibitors are IL-1 family antagonists, while others are IL-1R family members acting as membrane-bound or soluble decoy receptors. An imbalance between agonist and antagonist levels can lead to exaggerated inflammatory responses. Several genetic modifications or mutations associated with dysregulated IL-1 activity and autoinflammatory disorders were identified in mouse models and in patients. These findings paved the road to the successful use of IL-1 inhibitors in diseases that were previously considered as untreatable.