Unmasking of a protective tumor necrosis factor receptor I-mediated signal in the collagen-induced arthritis model

Arthritis Rheum. 2009 Feb;60(2):408-18. doi: 10.1002/art.24260.


Objective: To examine the relative importance of tumor necrosis factor receptor I (TNFRI) signaling in the hematopoietic tissue compartment in the progression of collagen-induced arthritis (CIA), a model of rheumatoid arthritis (RA).

Methods: DBA/1 mice were administered a lethal radiation dose and were then rescued with bone marrow derived from either DBA/1 or TNFRI(-/-) mice. CIA was then induced, and disease progression was characterized.

Results: Surprisingly, mice with CIA that received TNFRI(-/-) donor marrow developed increased disease severity as compared with control mice with CIA. This could not be attributed to an increased primary response to collagen or to the contribution of a non-DBA genetic background. In mice that received TNFRI(-/-) bone marrow, histologic markers of advanced disease were evident shortly after initiation of the immune response to collagen and long before clinical evidence of disease. Serum TNFalpha was undetectable, whereas serum interleukin-12 p40 levels were increased, at the end point of the study in mice that received TNFRI(-/-) bone marrow.

Conclusion: These data raise the intriguing possibility of the existence of an antiinflammatory, TNFRI-mediated circuit in the hematopoietic compartment. This circuit bears a resemblance to the switch in TNFalpha function that has been observed during the resolution of bacterial infections. These data suggest that TNFRI-mediated signals in the radioresistant tissues contribute to disease progression, whereas TNFRI-mediated signals in the radiosensitive tissues can contribute to protection from disease. We thus put forward the hypothesis that the degree of response to TNFalpha blockade in RA is dependent in part on the relative genetic strengths of these 2 pathways.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Experimental / metabolism*
  • Arthritis, Experimental / pathology
  • Arthritis, Experimental / physiopathology
  • Arthritis, Rheumatoid / metabolism*
  • Arthritis, Rheumatoid / pathology
  • Arthritis, Rheumatoid / physiopathology
  • Bone Marrow Transplantation
  • Bone Resorption
  • Male
  • Mice
  • Mice, Inbred DBA
  • Mice, Knockout
  • Radiation Chimera / metabolism
  • Radiation Injuries, Experimental / therapy
  • Receptors, Tumor Necrosis Factor, Type I / genetics
  • Receptors, Tumor Necrosis Factor, Type I / metabolism*
  • Severity of Illness Index
  • Signal Transduction
  • Tumor Necrosis Factor-alpha / metabolism*


  • Receptors, Tumor Necrosis Factor, Type I
  • Tumor Necrosis Factor-alpha