title: 1,25-dihydroxyvitamin D3 modulates Th17 polarization and interleukin-22 expression by memory T cells from patients with early rheumatoid arthritis.
abstract: OBJECTIVE
  To examine the immunologic mechanism by which 1,25-dihydroxyvitamin D(3) (1,25[OH](2)D(3)) may prevent corticosteroid-induced osteoporosis in patients with early rheumatoid arthritis (RA), with a focus on T cell biology.
  
  
  METHODS
  Peripheral blood mononuclear cells (PBMCs) and CD4+CD45RO+ (memory) and CD4+CD45RO- (non-memory) T cells separated by fluorescence-activated cell sorting (FACS) from treatment-naive patients with early RA were stimulated with anti-CD3/anti-CD28 in the absence or presence of various concentrations of 1,25(OH)(2)D(3), dexamethasone (DEX), and 1,25(OH)(2)D(3) and DEX combined. Levels of T cell cytokines were determined by enzyme-linked immunosorbent assay and flow cytometry.
  
  
  RESULTS
  The presence of 1,25(OH)(2)D(3) reduced interleukin-17A (IL-17A) and interferon-gamma levels and increased IL-4 levels in stimulated PBMCs from treatment-naive patients with early RA. In addition, 1,25(OH)(2)D(3) had favorable effects on tumor necrosis factor alpha (TNFalpha):IL-4 and IL-17A:IL-4 ratios and prevented the unfavorable effects of DEX on these ratios. Enhanced percentages of IL-17A- and IL-22-expressing CD4+ T cells and IL-17A-expressing memory T cells were observed in PBMCs from treatment-naive patients with early RA as compared with healthy controls. Of note, we found no difference in the percentage of CD45RO+ and CD45RO- cells between these 2 groups. Interestingly, 1,25(OH)(2)D(3), in contrast to DEX, directly modulated human Th17 polarization, accompanied by suppression of IL-17A, IL-17F, TNFalpha, and IL-22 production by memory T cells sorted by FACS from patients with early RA.
  
  
  CONCLUSIONS
  These data indicate that 1,25(OH)(2)D(3) may contribute its bone-sparing effects in RA patients taking corticosteroids by the modulation of Th17 polarization, inhibition of Th17 cytokines, and stimulation of IL-4.
authors.affiliation: Erasmus MC, University Medical Center, Department of Rheumatology, Rotterdam, The Netherlands. e.colin@erasmusmc.nl
authors.forename: E M
authors.initials: EM
authors.lastname: Colin
authors.forename: P S
authors.initials: PS
authors.lastname: Asmawidjaja
authors.forename: J P
authors.initials: JP
authors.lastname: van Hamburg
authors.forename: A M C
authors.initials: AM
authors.lastname: Mus
authors.forename: M
authors.initials: M
authors.lastname: van Driel
authors.forename: J M W
authors.initials: JM
authors.lastname: Hazes
authors.forename: J P T M
authors.initials: JP
authors.lastname: van Leeuwen
authors.forename: E
authors.initials: E
authors.lastname: Lubberts
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D002117:Calcitriol / Q000494:pharmacology*; D016764:Cell Polarity / Q000187:drug effects / Q000276:immunology; D002469:Cell Separation; D003907:Dexamethasone / Q000494:pharmacology; D004338:Drug Combinations; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007156:Immunologic Memory; D020381:Interleukin-17 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008297:Male; D008875:Middle Aged; D055815:Young Adult; D000097043:Interleukin-22
chemical_list: D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D017252:CD3 Complex; D002117:Calcitriol; D003907:Dexamethasone; D004338:Drug Combinations; D020381:Interleukin-17; D007378:Interleukins; D000097043:Interleukin-22