Caerulomycin A enhances the TGF-{beta}-Smad3 signalling by suppressing IFN-{gamma}-STAT1 signalling to expand Tregs [Cell Biology]

May 8th, 2014 by Gurram, R. K., Kujur, W., Maurya, S. K., Agrewala, J. N.

Cytokines play 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 cytokine milieu. In the present 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 upregulated the pool of Tregs, as evidenced by increased frequency of CD4+ Foxp3+ cells. In addition, CaeA significantly suppressed the number of Th1 and Th17 cells, as supported by decreased percentage of CD4+/IFN-γ+ and CD4+/IL-17+ cells, respectively. Further, we established the mechanism and observed that CaeA interfered with IFN-γ induced STAT1 signalling by augmenting SOCS1 expression. The increase in the TGF-β mediated Smad3 activity was also noted. Furthermore, CaeA rescued the Tregs from IFN-γ induced inhibition. These results were corroborated by blocking Smad3 activity, which abolished CaeA facilitated generation of Tregs. In essence, our results indicate a novel role of CaeA by inducing the generation of Tregs. This finding suggests that CaeA has enough potential to be considered as a potent future drug for treatment of autoimmunity.