The importance of IL-1 beta and TNF-alpha, and the noninvolvement of IL-6, in the development of monoclonal antibody-induced arthritis.
Injection of anti-type II collagen Ab and LPS induces arthritis in mice. The levels of IL-1 beta, IL-6, and chemokines (macrophage inflammatory protein (MIP)-1 alpha, MIP-2, and monocyte chemoattractant protein-1) in the hind paws increased with the onset of arthritis and correlated highly with arthritis scores. The level of TNF-alpha was also elevated, but only transiently. Quantitative real-time PCR analysis revealed increases in cytokine and chemokine mRNA. To elucidate the contribution of inflammatory cytokines and chemokines in arthritis development more directly, recombinant proteins, neutralizing Abs, and knockout mice were used. The injection of rIL-1 beta or TNF-alpha, but not IL-6 or chemokines, induced arthritis when mice were i.v. preinjected with anti-type II collagen Ab. However, a single injection of recombinant cytokines or chemokines into the hind paws did not induce swelling. Arthritis development was inhibited by neutralizing Ab against IL-1 beta, TNF-alpha, or MIP-1 alpha. In contrast, the inhibitory effect by anti-MIP-2 Ab was partial and, surprisingly, Abs to IL-6 and monocyte chemoattractant protein-1 showed no inhibitory effect. Furthermore, arthritis development in IL-1R(-/-) mice and TNFR(-/-) mice was not observed at all, but severe arthritis was developed in IL-6(-/-) mice. These results suggest that IL-1 beta and TNF-alpha play more crucial roles than IL-6 or chemokines in this model. Because arthritis was also developed in SCID mice, the development of arthritis in the Ab-induced mice model is due to a mechanism that does not involve T or B cells.
Biological Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan. tkagar@shina.sankyo.ac.jp
Takashi
T
Kagari
Hiromi
H
Doi
Takaichi
T
Shimozato
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D001168:Arthritis / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D054426:Chemokine CXCL2; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D024043:Collagen Type II / Q000276:immunology; D007375:Interleukin-1 / Q000235:genetics / Q000502:physiology*; D015850:Interleukin-6 / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D012333:RNA, Messenger / Q000032:analysis; D017472:Receptors, Interleukin-1 / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D000911:Antibodies, Monoclonal; D018932:Chemokine CCL2; D054426:Chemokine CXCL2; D018925:Chemokines; D024043:Collagen Type II; C404915:Cxcl2 protein, mouse; D007375:Interleukin-1; D015850:Interleukin-6; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D014409:Tumor Necrosis Factor-alpha