Sodium Benzoate, a Food Additive and a Metabolite of Cinnamon, Enriches Regulatory T Cells via STAT6-Mediated Upregulation of TGF-β.
Upregulation and/or maintenance of regulatory T cells (Tregs) during autoimmune insults may have therapeutic efficacy in autoimmune diseases. Earlier we have reported that sodium benzoate (NaB), a metabolite of cinnamon and a Food and Drug Administration-approved drug against urea cycle disorders, upregulates Tregs and protects mice from experimental allergic encephalomyelitis, an animal model of multiple sclerosis. However, mechanisms by which NaB increases Tregs are poorly understood. Because TGF-β is an important inducer of Tregs, we examined the effect of NaB on the status of TGF-β. In this study, we demonstrated that NaB induced the expression of TGF-β mRNA and protein in normal as well as proteolipid protein-primed splenocytes. The presence of a consensus STAT6 binding site in the promoter of the TGF-β gene, activation of STAT6 in splenocytes by NaB, recruitment of STAT6 to the TGF-β promoter by NaB, and abrogation of NaB-induced expression of TGF-β in splenocytes by small interfering RNA knockdown of STAT6 suggest that NaB induces the expression of TGF-β via activation of STAT6. Furthermore, we demonstrated that blocking of TGF-β by neutralizing Abs abrogated NaB-mediated protection of Tregs and experimental allergic encephalomyelitis. These studies identify a new function of NaB in upregulating TGF-β via activation of STAT6, which may be beneficial in MS patients.
Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612.
Madhuchhanda
M
Kundu
Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612.
Susanta
S
Mondal
Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612.
Avik
0000-0003-0523-8504
A
Roy
Department of Immunology, Rush University Medical Center, Chicago, IL 60612; and.
Jeffrey L
JL
Martinson
Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612; Kalipada_Pahan@rush.edu.|Division of Research and Development, Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60612.
Kalipada
K
Pahan
D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D002478:Cells, Cultured; D002935:Cinnamomum zeylanicum / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000628:therapy; D005260:Female; D005520:Food Preservatives / Q000627:therapeutic use*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000276:immunology* / Q000628:therapy; D018991:Myelin Proteolipid Protein / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D011401:Promoter Regions, Genetic / Q000235:genetics; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D020160:Sodium Benzoate / Q000378:metabolism / Q000627:therapeutic use*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D019138:Antibodies, Blocking; D005520:Food Preservatives; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D016212:Transforming Growth Factor beta; C435023:myelin proteolipid protein (139-151); D020160:Sodium Benzoate