Blockade of the interleukin-21/interleukin-21 receptor pathway ameliorates disease in animal models of rheumatoid arthritis

Arthritis Rheum. 2007 Apr;56(4):1152-63. doi: 10.1002/art.22452.


Objective: Interleukin-21 (IL-21) is a T cell-derived cytokine that modulates T cell, B cell, and natural killer cell responses. In this study, the effects of blocking IL-21 were examined in 2 rodent models of rheumatoid arthritis (RA) to determine whether IL-21 contributes to their pathologic processes.

Methods: DBA/1 mice were immunized with bovine type II collagen and then treated with murine IL-21 receptor Fc fusion protein (IL-21R.Fc), which was initiated after the onset of arthritis symptoms in 10% of the cohort. The mice were assessed 3 times per week for signs of disease, including histologic features as well as serum cytokine, Ig, and cytokine messenger RNA (mRNA) levels in the paws. In a separate experiment, Lewis rats were immunized with Freund's complete adjuvant followed by administration of IL-21R.Fc at the peak of inflammation in the joints. Rats were assessed daily for histologic features and for scoring of arthritis severity. In addition, the effects of IL-21R.Fc on the production of interferon-gamma (IFNgamma) by T cells were examined.

Results: Treatment of DBA/1 mice with IL-21R.Fc reduced the clinical and histologic signs of collagen-induced arthritis. Nonspecific IgG1 levels were decreased in response to treatment. The levels of IL-6 mRNA in the paws and the serum IL-6 levels were decreased after treatment with IL-21R.Fc. IFNgamma mRNA levels were increased in the paws, and the addition of IL-21R.Fc to collagen-activated lymph node cultures enhanced the levels of IFNgamma. Collagen-specific spleen cell responses in IL-21R.Fc-treated mice were observed as reduced levels of IFNgamma and increased levels of IL-6. Treatment of Lewis rats with IL-21R.Fc after induction of adjuvant-induced arthritis resulted in reversal of disease signs and improvements in histologic parameters.

Conclusion: These findings demonstrate a pathogenic role for IL-21 in animal models of RA, and support consideration of IL-21 as a therapeutic target in human RA.

MeSH terms

  • Animals
  • Arthritis, Experimental / metabolism
  • Arthritis, Experimental / pathology
  • Arthritis, Experimental / prevention & control*
  • Cells, Cultured
  • Cytokines / blood
  • Cytokines / genetics
  • Dose-Response Relationship, Drug
  • Gene Expression
  • Immunoglobulin Fc Fragments / administration & dosage*
  • Interleukin-21 Receptor alpha Subunit / administration & dosage*
  • Interleukin-21 Receptor alpha Subunit / metabolism
  • Interleukins / antagonists & inhibitors*
  • Interleukins / metabolism
  • Lymph Nodes / drug effects
  • Lymph Nodes / metabolism
  • Lymphocyte Activation
  • Male
  • Mice
  • Mice, Inbred DBA
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Inbred Lew
  • Rats, Sprague-Dawley
  • Receptors, Interleukin-21 / antagonists & inhibitors*
  • Receptors, Interleukin-21 / metabolism
  • Receptors, Tumor Necrosis Factor / administration & dosage
  • Receptors, Tumor Necrosis Factor / antagonists & inhibitors
  • Receptors, Tumor Necrosis Factor / genetics
  • Recombinant Fusion Proteins / administration & dosage*
  • Spleen / drug effects
  • Spleen / metabolism
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / metabolism


  • Cytokines
  • Il21r protein, mouse
  • Immunoglobulin Fc Fragments
  • Interleukin-21 Receptor alpha Subunit
  • Interleukins
  • RNA, Messenger
  • Receptors, Interleukin-21
  • Receptors, Tumor Necrosis Factor
  • Recombinant Fusion Proteins
  • interleukin-21