title: Uremic toxin indoxyl 3-sulfate regulates the differentiation of Th2 but not of Th1 cells to lessen allergic asthma.
abstract: Immune system dysfunctions including the increased Th1/Th2 ratio are common in chronic kidney disease (CKD) patients, and a wide variety of skin diseases including Th1-mediated uremic pruritis are associated with CKD. Although there are more than 90 uremic toxins reported, it is yet to be known which uremic solute is associated with the unbalanced Th1/Th2 ratio and how it works. Indoxyl 3-sulfate (I3S), one of uremic toxins and a potent aryl hydrocarbon receptor (AhR) ligand, accumulates in blood and tissues, increasing up to 81.04 μM in CKD patients, compared with 1.03 μM in healthy subjects. I3S activates NF-κB and AhR. Thus, we investigated roles of I3S in the differentiation of Th1 and Th2 cells. I3S inhibited Th2 differentiation but showed little or no effect on Th1 differentiation. I3S suppressed Th2-mediated ovalbumin-induced allergic asthma in mice and decreased the frequency of IL-4 producing CD4 T cells in the lungs. I3S inhibited phosphorylation of STAT5 and STAT6, transcription factors associated with Th2 differentiation. Effects of I3S on Th2 differentiation were suppressed by α-naphtoflavone, an AhR antagonist, indicating that I3S regulates Th2 differentiation AhR-dependently.
authors.affiliation: Department of Biology, Changwon National University, Kyungnam, Changwon, 641-773, South Korea.
authors.forename: You-Jung
authors.initials: YJ
authors.lastname: Hwang
authors.affiliation: Department of Biology, Changwon National University, Kyungnam, Changwon, 641-773, South Korea.
authors.forename: Mi-Ok
authors.initials: MO
authors.lastname: Yun
authors.affiliation: Department of Biology, Changwon National University, Kyungnam, Changwon, 641-773, South Korea.
authors.forename: Kyu-Tae
authors.initials: KT
authors.lastname: Jeong
authors.affiliation: Department of Biology, Changwon National University, Kyungnam, Changwon, 641-773, South Korea. Electronic address: parkjh@changwon.ac.kr.
authors.forename: Joo-Hung
authors.initials: JH
authors.lastname: Park
mesh_terms: D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism* / Q000517:prevention & control; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D001571:Benzoflavones / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D007073:Immunoglobulin E / Q000097:blood; D007200:Indican / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin; D010766:Phosphorylation; D011657:Pulmonary Eosinophilia / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism*; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D014511:Uremia / Q000276:immunology / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D001571:Benzoflavones; D007073:Immunoglobulin E; D007200:Indican; D015847:Interleukin-4; D010047:Ovalbumin; D018336:Receptors, Aryl Hydrocarbon; D050799:STAT5 Transcription Factor; D050800:STAT6 Transcription Factor; C484722:Ahr protein, mouse; C494100:Stat6 protein, mouse; C011512:alpha-naphthoflavone
keywords: AhR; I3S; Indoxyl 3-sulfate; STAT; STAT5; STAT6; Th; Th2; aryl hydrocarbon receptor; helper T cell; indoxyl 3-sulfate; signal transducer and activator of transcription; α-Naphtoflavone