title: Tumor necrosis factor alpha blockade exacerbates murine psoriasis-like disease by enhancing Th17 function and decreasing expansion of Treg cells.
abstract: OBJECTIVE
  Patients with psoriasis and psoriatic arthritis respond well to tumor necrosis factor alpha (TNFalpha) blockers in general; however, there is now mounting evidence that a small cohort of patients with rheumatoid arthritis who receive TNFalpha blockers develop psoriasis. This study was undertaken to explore the mechanisms underlying TNFalpha blockade-induced exacerbation of skin inflammation in murine psoriasis-like skin disease.
  
  
  METHODS
  Skin inflammation was induced in BALB/c scid/scid mice after they received CD4+CD45RB(high)CD25- (naive CD4) T cells from donor mice. These mice were treated with either anti-interleukin-12 (anti-IL-12)/23p40 antibody or murine TNFRII-Fc fusion protein and were examined for signs of disease, including histologic features, various cytokine levels in the serum, and cytokine or FoxP3 transcripts in the affected skin and draining lymph node (LN) cells. In a separate study, naive CD4+ T cells were differentiated into Th1 or Th17 lineages with anti-CD3/28 magnetic beads and appropriate cytokines in the presence or absence of TNFalpha. Cytokine gene expression from these differentiated cells was also determined.
  
  
  RESULTS
  Neutralization of TNFalpha exacerbated skin inflammation and markedly enhanced the expression of the proinflammatory cytokines IL-1beta, IL-6, IL-17, IL-21, and IL-22 but suppressed FoxP3 expression in the skin and reduced the number of FoxP3-positive Treg cells in the draining LNs. TNFalpha also demonstrated a divergent role during priming and reactivation of naive T cells.
  
  
  CONCLUSIONS
  These results reveal a novel immunoregulatory role of TNFalpha on Th17 and Treg cells in some individuals, which may account for the exacerbation of skin inflammation in some patients who receive anti-TNF treatments.
authors.affiliation: Wyeth Research, Cambridge, MA, USA.
authors.forename: Hak-Ling
authors.initials: HL
authors.lastname: Ma
authors.forename: Lee
authors.initials: L
authors.lastname: Napierata
authors.forename: Nancy
authors.initials: N
authors.lastname: Stedman
authors.forename: Stephen
authors.initials: S
authors.lastname: Benoit
authors.forename: Mary
authors.initials: M
authors.lastname: Collins
authors.forename: Cheryl
authors.initials: C
authors.lastname: Nickerson-Nutter
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Young
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D053759:Interleukin-23 / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D011565:Psoriasis / Q000276:immunology* / Q000503:physiopathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000097043:Interleukin-22; D000098546:Interleukin-21
chemical_list: D000906:Antibodies; D051858:Forkhead Transcription Factors; D018664:Interleukin-12; D020381:Interleukin-17; D053583:Interleukin-1beta; D053759:Interleukin-23; D015850:Interleukin-6; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; D000097043:Interleukin-22; D000098546:Interleukin-21; C498833:Foxp3 protein, mouse