title: Serum amyloid A induces mitogenic signals in regulatory T cells via monocyte activation.
abstract: Serum amyloid A (SAA) has recently been identified by our group as a mitogen for regulatory T cells (Treg). However, the molecular mechanism by which SAA induces Treg proliferation is unknown. Here we provide evidence that IL-1β and IL-6 are directly involved in the SAA-mediated proliferation of Treg. By engaging its several cognate receptors, SAA induces IL-1β and IL-6 secretion by monocytes and drives them toward an HLA-DR(hi) HVEM(lo) phenotype resembling immature dendritic cells, which have been implicated in tolerance generation. This monocyte-derived cytokine milieu is required for Treg expansion, as inhibition of IL-1β and IL-6 abrogate the ability of SAA to induce Treg proliferation. Furthermore, both IL-1β and IL-6 are required for ERK1/2 and AKT signaling in proliferating Treg. Collectively, these results point to a novel mechanism, by which SAA initiates a monocyte-dependent process that drives mitogenic signals in Treg.
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: kdnguyen@stanford.edu.
authors.forename: Khoa D
authors.initials: KD
authors.lastname: Nguyen
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Macaubas
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Phi
authors.initials: P
authors.lastname: Truong
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Tieying
authors.initials: T
authors.lastname: Hou
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Taejin
authors.initials: T
authors.lastname: Yoon
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: mellins@stanford.edu.
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Mellins
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology / Q000378:metabolism; D006684:HLA-DR Antigens / Q000276:immunology; D006801:Humans; D053583:Interleukin-1beta / Q000276:immunology* / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008934:Mitogens / Q000276:immunology; D009000:Monocytes / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000276:immunology; D000685:Serum Amyloid A Protein / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D006684:HLA-DR Antigens; C508600:IL6 protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; D008934:Mitogens; C521404:SAA1 protein, human; D050796:STAT3 Transcription Factor; D000685:Serum Amyloid A Protein; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: IL-1β; IL-6; Monocytes; Regulatory T cells; Serum amyloid A