Cytokine-dependent but acquired immunity-independent arthritis caused by DNA escaped from degradation.
DNase II digests the chromosomal DNA in macrophages after apoptotic cells and nuclei from erythroid precursors are engulfed. The DNase II-null mice develop a polyarthritis that resembles rheumatoid arthritis. Here, we showed that when bone marrow cells from the DNase II-deficient mice were transferred to the wild-type mice, they developed arthritis. A deficiency of Rag2 or a lack of lymphocytes accelerated arthritis of the DNase II-null mice, suggesting that the DNase II(-/-) macrophages were responsible for triggering arthritis, and their lymphocytes worked protectively. A high level of TNFα, IL-1β, and IL-6 was found in the affected joints of the DNase II-null mice, suggesting an inflammatory-skewed cytokine storm was established in the joints. A lack of TNFα, IL-1β, or IL-6 gene blocked the expression of the other cytokine genes as well and inhibited the development of arthritis. Neutralization of TNFα, IL-1β, or IL-6 had a therapeutic effect on the developed arthritis of the DNase II-null mice, indicating that the cytokine storm was essential for the maintenance of arthritis in the DNase II-deficient mice. Methotrexate, an antimetabolite that is often used to treat patients with rheumatoid arthritis, had a therapeutic effect with the DNase II-null mice. These properties of arthritis in the DNase II-null mice were similar to those found in human systemic-onset juvenile idiopathic arthritis or Still's disease, indicating that the DNase II-null mice are a good animal model of this type of arthritis.
Department of Medical Chemistry, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.
Kohki
K
Kawane
Hiromi
H
Tanaka
Yusuke
Y
Kitahara
Shin
S
Shimaoka
Shigekazu
S
Nagata
D000818:Animals; D001168:Arthritis / Q000209:etiology*; D016207:Cytokines / Q000032:analysis*; D004247:DNA / Q000378:metabolism; D004195:Disease Models, Animal; D004706:Endodeoxyribonucleases / Q000172:deficiency*; D008214:Lymphocytes / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D008727:Methotrexate / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D018345:Mice, Knockout
D016207:Cytokines; D004247:DNA; D004706:Endodeoxyribonucleases; C019329:deoxyribonuclease II; D008727:Methotrexate