title: IL-12p35 promotes antibody-induced joint inflammation by activating NKT cells and suppressing TGF-beta.
abstract: 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-12Rbeta(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-12Rbeta(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-12beta(2) receptors. Furthermore, the adoptive transfer of splenocytes from B6 or Gr-1(+) granulocyte-depleted mice restored joint inflammation in IL-12Rbeta(2)(-/-) mice as much as in B6 mice, whereas splenocytes from Jalpha18(-/-) mice did not. These findings indicate that signals via IL-12beta(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.
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-799, Seoul, South Korea.
authors.forename: Yuna
authors.initials: Y
authors.lastname: Park
authors.forename: Hye Sung
authors.initials: HS
authors.lastname: Kim
authors.forename: Ji Ye
authors.initials: JY
authors.lastname: Ahn
authors.forename: Daesun
authors.initials: D
authors.lastname: Yun
authors.forename: Mi La
authors.initials: ML
authors.lastname: Cho
authors.forename: Seokmann
authors.initials: S
authors.lastname: Hong
authors.forename: Ho Youn
authors.initials: HY
authors.lastname: Kim
authors.forename: Doo Hyun
authors.initials: DH
authors.lastname: Chung
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D001169:Arthritis, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D055879:Gene Knock-In Techniques; D007105:Immune Complex Diseases / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007106:Immune Sera / Q000008:administration & dosage* / Q000097:blood; D018836:Inflammation Mediators / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000502:physiology; D053765:Interleukin-12 Subunit p35 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D053707:Receptors, Interleukin-12 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; C508439:IL12RB2 protein, human; D007106:Immune Sera; D018836:Inflammation Mediators; D053765:Interleukin-12 Subunit p35; D053707:Receptors, Interleukin-12; D016212:Transforming Growth Factor beta