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)

Gurram, Rama Krishna ; Kujur, Weshely ; Maurya, Sudeep K. ; Agrewala, Javed N. (2014) 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) Journal of Biological Chemistry, 289 (25). pp. 17515-17528. ISSN 0021-9258

[img]
Preview
PDF - Other
4MB

Official URL: http://www.jbc.org/content/289/25/17515.long

Related URL: http://dx.doi.org/10.1074/jbc.M113.545871

Abstract

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.

Item Type:Article
Source:Copyright of this article belongs to American Society for Biochemistry and Molecular Biology.
Keywords:Immunology; Immunosuppression; Immunotherapy; Smad Transcription Factor; Stat Transcription Factor; T Cell
ID Code:101700
Deposited On:17 Jan 2017 10:59
Last Modified:17 Jan 2017 10:59

Repository Staff Only: item control page