IL-12p40 Homodimer Ameliorates Experimental Autoimmune Arthritis.
IL-23 is the key cytokine that induces the expansion of Th17 cells. It is composed of p19 and p40 subunits of IL-12. The p40 subunit binds competitively to the receptor of IL-23 and blocks its activity. Our aim was to assess the preventive and therapeutic effect of the IL-12p40 homodimer (p40)2 subunit in autoimmune arthritis animal models. In the current study, using IL-1R antagonist-knockout mice and a collagen-induced arthritis model, we investigated the suppressive effect of (p40)2 on inflammatory arthritis. We demonstrated that the recombinant adenovirus-expressing mouse (p40)2 model prevented the development of arthritis when given before the onset of arthritis. It also decreased the arthritis index and joint erosions in the mouse model if transferred after arthritis was established. (p40)2 inhibited the production of inflammatory cytokines and Ag-specific T cell proliferation. It also induced CD4(+)CD25(+)Foxp3 regulatory T (Treg) cells in vitro and in vivo, whereas the generation of retinoic acid receptor-related organ receptor γt and Th17 cells was suppressed. The induction of Treg cells and the suppression of Th17 cells were mediated via activated STAT5 and suppressed STAT3. Our data suggest that (p40)2 suppressed inflammatory arthritis successfully. This could be a useful therapeutic approach in autoimmune arthritis to regulate the Th17/Treg balance and IL-23 signaling.
Rheumatism Research Center, Catholic Research Institutes of Medical Science, Catholic University of Korea, Seoul 137-701, Republic of Korea; Laboratory of Immune Network, Conversant Research Consortium in Immunologic Disease, Catholic University of Korea, Seoul 137-701, Republic of Korea;
Seon-Yeong
SY
Lee
Division of Rheumatology, Department of Internal Medicine, Hallym University Kang-Nam Sacred Heart Hospital, Seoul 150-950, Republic of Korea; and.
Young Ok
YO
Jung
Integrative Bioscience and Biotechnology, World Class University, Pohang University of Science and Technology Biotechnology Center, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea.
Doo-Jin
DJ
Kim
Rheumatism Research Center, Catholic Research Institutes of Medical Science, Catholic University of Korea, Seoul 137-701, Republic of Korea;
Chang-Min
CM
Kang
Rheumatism Research Center, Catholic Research Institutes of Medical Science, Catholic University of Korea, Seoul 137-701, Republic of Korea; Laboratory of Immune Network, Conversant Research Consortium in Immunologic Disease, Catholic University of Korea, Seoul 137-701, Republic of Korea;
Young-Mee
YM
Moon
Rheumatism Research Center, Catholic Research Institutes of Medical Science, Catholic University of Korea, Seoul 137-701, Republic of Korea;
Yu-Jung
YJ
Heo
Rheumatism Research Center, Catholic Research Institutes of Medical Science, Catholic University of Korea, Seoul 137-701, Republic of Korea;
Hye-Jwa
HJ
Oh
Integrative Bioscience and Biotechnology, World Class University, Pohang University of Science and Technology Biotechnology Center, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea.
Seong-Jeong
SJ
Park
Integrative Bioscience and Biotechnology, World Class University, Pohang University of Science and Technology Biotechnology Center, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea.
Se-Hwan
SH
Yang
Rheumatism Research Center, Catholic Research Institutes of Medical Science, Catholic University of Korea, Seoul 137-701, Republic of Korea;
Seung Ki
SK
Kwok
Rheumatism Research Center, Catholic Research Institutes of Medical Science, Catholic University of Korea, Seoul 137-701, Republic of Korea;
Ji-Hyeon
JH
Ju
Rheumatism Research Center, Catholic Research Institutes of Medical Science, Catholic University of Korea, Seoul 137-701, Republic of Korea;
Sung-Hwan
SH
Park
Integrative Bioscience and Biotechnology, World Class University, Pohang University of Science and Technology Biotechnology Center, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea.
Young Chul
YC
Sung
Rheumatism Research Center, Catholic Research Institutes of Medical Science, Catholic University of Korea, Seoul 137-701, Republic of Korea; iammila@catholic.ac.kr ho0919@catholic.ac.kr.
Ho-Youn
HY
Kim
Rheumatism Research Center, Catholic Research Institutes of Medical Science, Catholic University of Korea, Seoul 137-701, Republic of Korea; Laboratory of Immune Network, Conversant Research Consortium in Immunologic Disease, Catholic University of Korea, Seoul 137-701, Republic of Korea; iammila@catholic.ac.kr ho0919@catholic.ac.kr.
Mi-La
ML
Cho
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D053762:Interleukin-12 Subunit p40 / Q000276:immunology / Q000494:pharmacology*; D020381:Interleukin-17 / Q000096:biosynthesis; D053760:Interleukin-23 Subunit p19 / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000096:biosynthesis; D055503:Protein Multimerization; D018123:Receptors, Interleukin / Q000276:immunology; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*
D016207:Cytokines; C583355:IL1R1 protein, mouse; C098680:Il17a protein, mouse; C508841:Il23a protein, mouse; D053762:Interleukin-12 Subunit p40; D020381:Interleukin-17; D053760:Interleukin-23 Subunit p19; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D018123:Receptors, Interleukin; D053573:Receptors, Interleukin-1 Type I; C539739:Rora protein, mouse; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C494087:Stat3 protein, mouse; C494093:Stat5a protein, mouse; D003094:Collagen