Distinct contribution of IL-6, TNF-α, IL-1, and IL-10 to T cell–mediated spontaneous autoimmune arthritis in mice
Hiroshi Hata, … , Takashi Nakamura, Shimon Sakaguchi
Hiroshi Hata, … , Takashi Nakamura, Shimon Sakaguchi
Published August 16, 2004
Citation Information: J Clin Invest. 2004;114(4):582-588. https://doi.org/10.1172/JCI21795.
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Article Autoimmunity

Distinct contribution of IL-6, TNF-α, IL-1, and IL-10 to T cell–mediated spontaneous autoimmune arthritis in mice

Abstract

Cytokines play key roles in spontaneous CD4+ T cell–mediated chronic autoimmune arthritis in SKG mice, a new model of rheumatoid arthritis. Genetic deficiency in IL-6 completely suppressed the development of arthritis in SKG mice, irrespective of the persistence of circulating rheumatoid factor. Either IL-1 or TNF-α deficiency retarded the onset of arthritis and substantially reduced its incidence and severity. IL-10 deficiency, on the other hand, exacerbated disease, whereas IL-4 or IFN-γ deficiency did not alter the disease course. Synovial fluid of arthritic SKG mice contained high amounts of IL-6, TNF-α, and IL-1, in accord with active transcription of these cytokine genes in the afflicted joints. Notably, immunohistochemistry revealed that distinct subsets of synovial cells produced different cytokines in the inflamed synovium: the superficial synovial lining cells mainly produced IL-1 and TNF-α, whereas scattered subsynovial cells produced IL-6. Thus, IL-6, IL-1, TNF-α, and IL-10 play distinct roles in the development of SKG arthritis; arthritogenic CD4+ T cells are not required to skew to either Th1 or Th2; and the appearance of rheumatoid factor is independent of joint inflammation. The results also indicate that targeting not only each cytokine but also each cell population secreting distinct cytokines could be an effective treatment of rheumatoid arthritis.

Authors

Hiroshi Hata, Noriko Sakaguchi, Hiroyuki Yoshitomi, Yoichiroh Iwakura, Kenji Sekikawa, Yoshiaki Azuma, Chieko Kanai, Eiko Moriizumi, Takashi Nomura, Takashi Nakamura, Shimon Sakaguchi

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Development of arthritis in cytokine-deficient SKG mice. (A) Incidence a...
Development of arthritis in cytokine-deficient SKG mice. (A) Incidence and severity of arthritis in female SKG mice homozygously (–/–) (filled circles) or heterozygously (+/–) (open squares) deficient in indicated cytokines or cytokine-intact (+/+) (open triangles). Vertical bars represent the means ± SD of the whole group of mice. Arthritis scores are significantly different (P < 0.01) between IL-6+/+ and IL-6+/– mice at 19–32 weeks; between IL-6+/– and IL-6–/– mice at 16–32 weeks; between IL-1+/+ and IL-1+/– mice at 17–32 weeks; between IL-1–/– and IL-1+/– mice at 19–32 weeks; between TNF-α+/+ and TNF-α+/– mice at 15–32 weeks; between TNF-α–/– and TNF-α+/– mice at 21–32 weeks; between IL-10+/+ and IL-10+/– mice at 18–24 weeks; and between IL-10–/– and IL-10+/– mice at 12–24 weeks. (B–D) Histology of finger joints of a 32-week-old wild-type (B) or IL-6–deficient (C) or a 24-week-old IL-10–deficient SKG mouse (D) (original magnification, ×10).