title: 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).
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.
authors.affiliation: From the Immunology Laboratory, Institute of Microbial Technology (Council of Scientific and Industrial Research), Chandigarh 160036, India.
authors.forename: Rama Krishna
authors.initials: RK
authors.lastname: Gurram
authors.affiliation: From the Immunology Laboratory, Institute of Microbial Technology (Council of Scientific and Industrial Research), Chandigarh 160036, India.
authors.forename: Weshely
authors.initials: W
authors.lastname: Kujur
authors.affiliation: From the Immunology Laboratory, Institute of Microbial Technology (Council of Scientific and Industrial Research), Chandigarh 160036, India.
authors.forename: Sudeep K
authors.initials: SK
authors.lastname: Maurya
authors.affiliation: From the Immunology Laboratory, Institute of Microbial Technology (Council of Scientific and Industrial Research), Chandigarh 160036, India javed@imtech.res.in.
authors.forename: Javed N
authors.initials: JN
authors.lastname: Agrewala
mesh_terms: D000818:Animals; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D011725:Pyridines / Q000494:pharmacology*; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D051900:Smad3 Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D011725:Pyridines; D050794:STAT1 Transcription Factor; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C491590:Socs1 protein, mouse; C494080:Stat1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D016212:Transforming Growth Factor beta; C544423:caerulomycin A; D007371:Interferon-gamma
keywords: Immunology; Immunosuppression; Immunotherapy; SMAD Transcription Factor; STAT Transcription Factor; T Cell