title: Elevated frequencies of CD4(+) IL-21(+) T, CD4(+) IL-21R(+) T and IL-21(+) Th17 cells, and increased levels of IL-21 in bleomycin-induced mice may be associated with dermal and pulmonary inflammation and fibrosis.
abstract: OBJECTIVE
  Systemic sclerosis (SSc) is characterized by immune abnormalities, progressive fibrosis of the skin and internal organs, and microvascular injury and damage. Interleukin-21 receptor (IL-21R) is expressed in the epidermis from patients with SSc. However, information describing the role of IL-21 in SSc is limited.
  
  
  METHODS
  We established a mouse model of bleomycin (BLM)-induced fibrosis. The frequency of CD4(+) IL-21(+) T, CD4(+) IL-21R(+) T and IL-21(+) Th17 cells in peripheral blood, skin and lungs of BLM-induced mice were detected by flow cytometry; IL-21 levels in the peripheral blood were evaluated by enzyme-linked immunosorbent assay (ELISA). CD4(+) T cells were isolated from the spleen of BLM-induced and control mice and cultured in vitro alone or in the presence of mrIL-21 or mrIL-21 plus transforming growth factor (TGF)-β1. The frequency of Th17 cells was detected by flow cytometry; levels of IL-17 were evaluated by ELISA, and the expression of IL-17A and retinoic-acid-receptor-related orphan receptors gamma t (RORγt) messenger RNA were analyzed by real-time polymerase chain reaction.
  
  
  RESULTS
  Compared to control mice, the frequency of CD4(+) IL-21(+) T, CD4(+) 21R(+) T and IL-21(+) Th17 cells and the levels of IL-21 were significantly increased in BLM-induced mice. The frequency of CD4(+) IL-21(+) T, CD4(+) 21R(+) T and IL-21(+) Th17 cells and the levels of IL-21 were correlated with dermal and pulmonary inflammation and fibrosis. In vitro analyses indicate that IL-21 promoted the differentiation of Th17 cells from CD4(+) cells isolated from the spleen of BLM-induced mice.
  
  
  CONCLUSIONS
  IL-21 may play an important role in the pathogenesis of SSc as a Th17 effector cytokine, and IL-21 may induce the differentiation of Th17 cells in the BLM-induced SSc mouse model.
authors.affiliation: Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Lei
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
authors.forename: Zhi-Yi
authors.initials: ZY
authors.lastname: He
authors.affiliation: Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
authors.forename: Xue-Jiao
authors.initials: XJ
authors.lastname: Sun
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
authors.forename: Xiao-Ning
authors.initials: XN
authors.lastname: Zhong
mesh_terms: D000818:Animals; D001761:Bleomycin; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D003875:Drug Eruptions / Q000209:etiology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005355:Fibrosis; D006909:Hydroxyproline / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D053738:Interleukin-21 Receptor alpha Subunit / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D007378:Interleukins / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D008168:Lung / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008807:Mice, Inbred BALB C; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000276:immunology / Q000378:metabolism; D010641:Phenotype; D011014:Pneumonia / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D012595:Scleroderma, Systemic / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D012867:Skin / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism*; D015854:Up-Regulation; D000098546:Interleukin-21
chemical_list: C098680:Il17a protein, mouse; C508118:Il21r protein, mouse; D020381:Interleukin-17; D053738:Interleukin-21 Receptor alpha Subunit; D007378:Interleukins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539901:Rorc protein, mouse; D001761:Bleomycin; D000098546:Interleukin-21; D006909:Hydroxyproline
keywords: CD4+T cells; Systemic sclerosis; Th17 cells; interleukin-21; interleukin-21 receptor