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Caerulomycin A Enhances Transforming Growth Factor-β (TGF-β)-Smad3 Protein Signaling by Suppressing Interferon-γ (IFN-γ)-Signal Transducer and Activator of Transcription 1 (STAT1) Protein Signaling to Expand Regulatory T Cells (Tregs)*

R. Gurram,Weshely Kujur,S. K. Maurya,J. Agrewala

Published 2014 in Journal of Biological Chemistry

ABSTRACT

Background: Caerulomycin A, a known antifungal agent, was explored for its novel immunomodulatory activity. Results: Caerulomycin A supports the generation of Tregs by augmenting the TGF-β-Smad3 and suppressing the IFN-γ-STAT1 signaling pathways by enhancing SOCS1 expression. Conclusion: Caerulomycin A induces and enhances the Treg population. Significance: Caerulomycin A can be a potent future drug for treating autoimmune diseases by eliciting the generation of Tregs. Cytokines play a very important role in the regulation of immune homeostasis. Regulatory T cells (Tregs) responsible for the generation of peripheral tolerance are under the tight regulation of the cytokine milieu. In this study, we report a novel role of a bipyridyl compound, Caerulomycin A (CaeA), in inducing the generation of Tregs. It was observed that CaeA substantially up-regulated the pool of Tregs, as evidenced by an increased frequency of CD4+ Foxp3+ cells. In addition, CaeA significantly suppressed the number of Th1 and Th17 cells, as supported by a decreased percentage of CD4+/IFN-γ+ and CD4+/IL-17+ cells, respectively. Furthermore, we established the mechanism and observed that CaeA interfered with IFN-γ-induced STAT1 signaling by augmenting SOCS1 expression. An increase in the TGF-β-mediated Smad3 activity was also noted. Furthermore, CaeA rescued Tregs from IFN-γ-induced inhibition. These results were corroborated by blocking Smad3 activity, which abolished the CaeA-facilitated generation of Tregs. In essence, our results indicate a novel role of CaeA in inducing the generation of Tregs. This finding suggests that CaeA has enough potential to be considered as a potent future drug for the treatment of autoimmunity.

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