In recent studies,
SPA0355, a
thiourea analog, has been demonstrated to possess strong anti-inflammatory activity. However, the mechanisms underlying the effects of
SPA0355 on immune-mediated diseases have not been fully defined. The present study was designed to investigate the immunological and molecular mechanisms by which
SPA0355 modulates cluster of differentiation of (CD4)(+) T-cell-mediated immune responses in allergic airway
inflammation. In vitro studies have shown that
SPA0355 suppresses CD4(+) T-cell activation, proliferation, and differentiation via modulation of
T-cell receptor (TCR) signal transduction and
cytokine-induced
Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling. Next, we investigated the efficacy of
SPA0355 in
ovalbumin (OVA)-induced allergic airway
inflammation. Intraperitoneal administration of
SPA0355 inhibited inflammatory cell recruitment into the airways as well as the production of Th2
cytokines in bronchoalveolar fluid and suppressed OVA-induced
IgE production in serum. Additionally,
SPA0355 suppressed
mucin production and smooth muscle
hypertrophy and prevented the development of
airway hyperresponsiveness. Given that allergic airway
inflammation is mainly driven by Th2 cell responses, it is highly possible that the defects in CD4(+) T-cell activation and Th2 cell differentiation in the draining lymph nodes and suppressed NF-κB activation in the lungs of SPA0355-treated mice illustrate an immunological mechanism of the preventive effect of
SPA0355 on the aforementioned asthmatic characteristics. Collectively, our results suggest that
SPA0355 directly modulates Th1 and Th2 responses through the suppression of multiple signaling pathways triggered by TCR or
cytokine receptor stimulation, and that
SPA0355 has protective effects in a murine model of allergic airway
inflammation.