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.


CONCLUSIONS
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.
Koziczak-Holbro
Magdalena
M
Novartis Institutes for BioMedical Research, Basel, Switzerland.
Littlewood-Evans
Amanda
A
Pöllinger
Bernadette
B
Kovarik
Jiri
J
Dawson
Janet
J
Zenke
Gerhard
G
Burkhart
Christoph
C
Müller
Matthias
M
Gram
Hermann
H
D000818:Animals; D001168:Arthritis / Q000139:chemically induced / Q000276:immunology* / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D055879:Gene Knock-In Techniques; D007113:Immunity, Innate / Q000502:physiology*; D007074:Immunoglobulin G / Q000378:metabolism; D007375:Interleukin-1 / Q000502:physiology; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000502:physiology*; D008070:Lipopolysaccharides; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D009504:Neutrophils / Q000473:pathology / Q000502:physiology; D013601:T-Lymphocytes / Q000473:pathology / Q000502:physiology; D051193:Toll-Like Receptors / Q000502:physiology
D007074:Immunoglobulin G; D007375:Interleukin-1; D008070:Lipopolysaccharides; D051193:Toll-Like Receptors; D053592:Interleukin-1 Receptor-Associated Kinases