Interleukin-4 can be a key positive regulator of inflammatory arthritis.
OBJECTIVE
Development of arthritis in the K/BxN mouse model depends on the induction of high titers of antibodies against the enzyme glucose-6-phosphate isomerase (GPI), promoted by CD4(+) T cells expressing a GPI-specific transgenic T cell receptor (TCR). This study was undertaken to determine whether this strong autoantibody response depends on T cell differentiation to the Th1 or Th2 phenotype.


METHODS
The roles of Th cell-biasing cytokines were investigated by introducing the interleukin-4 (IL-4) and IL-12-specific subunit p35 (IL-12p35)-knockout mutations into the K/BxN model and evaluating the impact of these deficiencies on disease. The IL-4-expressing cell types in K/BxN mice were revealed by crossing in a knockin alteration, which resulted in green fluorescent protein expression controlled by endogenous IL-4 gene-regulatory elements. Transfer experiments permitted the identification of the IL-4-producing cell type required for arthritis, and quantitative reverse transcriptase-polymerase chain reaction allowed for determination of the cytokine profile of K/BxN T cells.


RESULTS
While IL-12p35 appeared dispensable for the development of arthritis, IL-4 was crucial for full development of disease. The GPI-reactive TCR of standard K/BxN mice induced the transcriptional activation of the IL-4 locus in CD4(+) T cells and eosinophils, and CD4(+) T cells were the obligatory source of IL-4 for disease. However, the cytokine profile of K/BxN T cells revealed that K/BxN arthritis is not a "pure" Th2 disease.


CONCLUSIONS
The K/BxN model, although not a classic Th2 disease, depends critically on IL-4. The potential of IL-4 to promote inflammatory arthritis should be considered when proposing therapies for rheumatoid arthritis aimed at biasing T cells toward IL-4 production.
Ohmura
Koichiro
K
Joslin Diabetes Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.
Nguyen
Linh T
LT
Locksley
Richard M
RM
Mathis
Diane
D
Benoist
Christophe
C
D000818:Animals; D001168:Arthritis / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology*; D051379:Mice; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
D001323:Autoantibodies; D018664:Interleukin-12; D015847:Interleukin-4