期刊
JOURNAL OF IMMUNOLOGY
卷 185, 期 3, 页码 1476-1484出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1000425
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资金
- Ministry of Education, Science and Technology [2005-0048481]
- National Research Foundation of Korea [2005-0048481] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
The functional role of IL-12 in rheumatoid arthritis is controversial. Moreover, whether IL-12 contributes to regulation of Ab-induced joint inflammation remains unclear. To address these issues, we explored the functional roles of IL-12 in Ab-induced arthritis using the K/BxN serum transfer model. IL-12p35(-/-) and IL-12R beta(-/-)(2) mice were resistant to the development of arthritis. Injection of K/BxN serum into IL-12p40-yellow fluorescence protein reporter (yet40) mice induced CD11b(+) cells, CD11c(+) cells, and Gr-1(+) granulocytes to produce IL-12p40 in the joints. The levels of IFN-gamma, IL-4, and IL-6 production were lower in joint tissues of IL-12p35(-/-) and IL-12R beta(-/-)(2) mice than in B6 mice, whereas levels of TGF-beta expression were higher. Administering IL-12p35(-/-) mice rIL-12 or IFN-gamma restored joint inflammation and suppressed TGF-beta production in joint tissues. Moreover, administering neutralizing anti-TGF-beta mAb enhanced joint inflammation. Among the immune cells that infiltrated joint tissues during Ab-induced arthritis, NKT cells expressed IL-12 beta(2) receptors. Furthermore, the adoptive transfer of splenocytes from B6 or Gr-1(+) granulocyte-depleted mice restored joint inflammation in IL-12R beta(-/-)(2) mice as much as in B6 mice, whereas splenocytes from J alpha 18(-/-) mice did not. These findings indicate that signals via IL-12 beta(2) receptors on NKT cells play a critical role in the development of Ab-induced arthritis. The IL-12p35/IFN-gamma axis promotes Ab-induced joint inflammation by activating NKT cells and suppressing TGF-beta, which may provide novel information for the development of new therapeutic strategies for the inhibition of rheumatoid arthritis. The Journal of Immunology, 2010, 185: 1476-1484.
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