title: Akt-dependent enhanced migratory capacity of Th17 cells from children with lupus nephritis.
abstract: Th17 cells infiltrate the kidneys of patients with lupus nephritis (LN) and are critical for the pathogenesis of this disease. In this study, we show that enhanced activity of Stat3 in CD4(+)CD45RA(-)Foxp3(-) and Foxp3(low) effector T cells from children with LN correlates with increased frequencies of IL-17-producing cells within these T cell populations. The levels of retinoic acid-related orphan receptor c and IL-17 mRNA are significantly higher in PBMCs from children with LN than in those from controls. Mammalian target of rapamycin inhibition by rapamycin reduces both Stat3 activation in effector T cells and the frequency of IL-17-producing T cells in lupus patients. Complement factor C5a slightly increases the expression of IL-17 and induces activation of Akt in anti-CD3-activated lupus effector T cells. Th17 cells from children with LN exhibit high Akt activity and enhanced migratory capacity. Inhibition of the Akt signaling pathway significantly decreases Th17 cell migration. These findings indicate that the Akt signaling pathway plays a significant role in the migratory activity of Th17 cells from children with LN and suggest that therapeutic modulation of the Akt activity may inhibit Th17 cell trafficking to sites of inflammation and thus suppress chronic inflammatory processes in children with LN.
authors.affiliation: Department of Pediatrics I, Innsbruck Medical University, A-6020 Innsbruck, Austria;
authors.forename: Sudhir
authors.initials: S
authors.lastname: Kshirsagar
authors.affiliation: Department of Pediatrics I, Innsbruck Medical University, A-6020 Innsbruck, Austria;
authors.forename: Magdalena
authors.initials: M
authors.lastname: Riedl
authors.affiliation: University Children's Hospital, Heidelberg, 69120 Heidelberg, Germany; University Children's Hospital, 72076 Tuebeingen, Germany;
authors.forename: Heiko
authors.initials: H
authors.lastname: Billing
authors.affiliation: University Children's Hospital, Heidelberg, 69120 Heidelberg, Germany;
authors.forename: Burkhard
authors.initials: B
authors.lastname: Tönshoff
authors.affiliation: Tyrolean Cancer Research Institute, Innsbruck Medical University, A-6020 Innsbruck, Austria;
authors.forename: Shanmugapriya
authors.initials: S
authors.lastname: Thangavadivel
authors.affiliation: Klinikum Links der Weser, 28277 Bremen, Germany;
authors.forename: Christian
authors.initials: C
authors.lastname: Steuber
authors.affiliation: Department of Pediatrics, University Children's Hospital, 18075 Rostock, Germany; and.
authors.forename: Hagen
authors.initials: H
authors.lastname: Staude
authors.affiliation: Department of Plastic, Aesthetic, and Reconstructive Surgery, Hospital of the Barmherzige Brüder Salzburg, Paracelsus Medical University, 5020 Salzburg, Austria.
authors.forename: Gottfried
authors.initials: G
authors.lastname: Wechselberger
authors.affiliation: Department of Pediatrics I, Innsbruck Medical University, A-6020 Innsbruck, Austria; monika.edelbauer@i-med.ac.at.
authors.forename: Monika
authors.initials: M
authors.lastname: Edelbauer
mesh_terms: D000293:Adolescent; D002465:Cell Movement / Q000187:drug effects; D002648:Child; D015936:Complement C5a / Q000235:genetics / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology; D007668:Kidney / Q000276:immunology / Q000473:pathology; D017493:Leukocyte Common Antigens / Q000235:genetics / Q000276:immunology; D008181:Lupus Nephritis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008297:Male; D061251:Primary Cell Culture; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000276:immunology; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007166:Immunosuppressive Agents; D020381:Interleukin-17; D018168:Receptors, Retinoic Acid; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015936:Complement C5a; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D017493:Leukocyte Common Antigens; D020123:Sirolimus