The critical role of kinase activity of interleukin-1 receptor-associated kinase 4 in animal models of joint inflammation.

OBJECTIVE: We have previously reported that the kinase activity of interleukin-1 receptor-associated kinase 4 (IRAK-4) is important for Toll-like receptor and interleukin-1 receptor signaling in vitro. Using mice devoid of IRAK-4 kinase activity (IRAK-4 KD mice), we undertook this study to determine the importance of IRAK-4 kinase function in complex disease models of joint inflammation.

METHODS: IRAK-4 KD mice were subjected to serum transfer-induced (K/BxN) arthritis, and migration of transferred spleen lymphocytes into joints and cartilage and bone degradation were assessed. T cell response in vivo was tested in antigen-induced arthritis (AIA) by measuring the T cell-dependent antigen-specific IgG production and frequency of antigen-specific T cells in the spleen and lymph nodes. T cell allogeneic response was tested in vitro by mixed lymphocyte reaction (MLR).

RESULTS: Lipopolysaccharide-induced local neutrophil influx into subcutaneous air pouches was impaired in IRAK-4 KD mice. These mice were also protected from inflammation in the K/BxN and AIA models, as shown by reduced swelling of joints. Histologic analysis of joints of K/BxN serum-injected mice revealed that bone erosion, osteoclast formation, and cartilage matrix proteoglycan loss were reduced in IRAK-4 KD mice. Assessment of T cell response by MLR, by frequency of antigen-specific clones, and by production of antigen-specific IgG did not reveal substantial differences between IRAK-4 KD and wild-type mice.

CONCLUSION: These results demonstrate that IRAK-4 is a key component for the development of proarthritis inflammation, but that it is not crucial for T cell activation. Therefore, the kinase function of IRAK-4 appears to be an attractive therapeutic target in chronic inflammation.