A recombinant IL-1ß vaccine attenuates bleomycin-induced pulmonary fibrosis in mice.

ABSTRACT

Interleukin-1ß (IL-1ß) contributes to interstitial lung disease (ILD) and pulmonary fibrosis (PF), thus representing a potential therapeutic target for PF. In this study, we first verified the increased expression of IL-1ß in human fibrotic lung specimens and mouse lung tissues after intratracheal (i.t.) instillation of bleomycin (BLM), after which the pro-inflammatory and pro-fibrotic effects of recombinant IL-1ß were tested in mice. The results above suggested that vaccination against IL-1ß could be an effective strategy for managing PF. An anti-IL-1ß vaccine (PfTrx-IL-1ß) was designed by incorporating two IL-1ß-derived polypeptides, which have been verified as the key domains that mediate the binding of IL-1ß to its type I receptor, into Pyrococcus furiosus thioredoxin (PfTrx). The fusion protein PfTrx-IL-1ß was prepared by using E. coli expression system. The vaccine was well tolerated; it induced robust and long-lasting antibody responses in mice and neutralized the biological activity of IL-1ß, as shown in cellular assays. Pre-immunization with PfTrx-IL-1ß effectively protected mice from BLM-induced lung injury, inflammation, and fibrosis. In vitro experiments further showed that anti-PfTrx-IL-1ß antibodies counteracted the effects of IL-1ß concerning pro-inflammatory and pro-fibrotic cytokine production by primary mouse lung fibroblast, macrophages (RAW264.7), and type II alveolar epithelial cell (A549), primary mouse lung fibroblast activation and epithelial-mesenchymal transition (EMT) of alveolar epithelial cells. In addition, the vaccination did not compromise the anti-infection immunity in mice, as validated by a sepsis model. Our preliminary study suggests that the anti-IL-1ß vaccine we prepared has the potential to be developed as a therapeutic measure for PF. Further experiments are warranted to evaluate whether IL-1ß vaccination has the capacity of inhibiting chronic progressive PF and reversing established PF.