A Broad Blockade of Signaling from the IL-20 Family of Cytokines Potently Attenuates Collagen-Induced Arthritis.
Two heterodimeric receptors consisting of either IL-20R1 or IL-22R1 in complex with a common β receptor subunit IL-20R2 are shared by three of the IL-20 family of cytokines: IL-19, IL-20, and IL-24. These proinflammatory cytokines have been implicated in the pathogenesis of some autoimmune diseases, including rheumatoid arthritis (RA), psoriasis, and atopic dermatitis. Although mAbs against IL-19 and IL-20 have each been shown to modulate disease severity of collagen-induced arthritis in animal models, and anti-IL-20 therapeutic Ab has exhibited some efficacy in the treatment of RA in clinical trials, benefits for a complete blockade of these functionally redundant cytokines remain to be explored. In this report, we show that recombinant human soluble IL-20R2-Fc fusion protein binds to IL-19, IL-20, and IL-24 with similar high affinity and blocks their signaling in vitro. In DBA/1 mouse collagen-induced arthritis model, recombinant human IL-20R2-Fc exhibits comparable efficacy as TNF blocker etanercept in the treatment of established arthritis, whereas the combined use of both biologics manifests little synergistic therapeutic effects. In situ ligand-receptor functional binding analysis shows that a large amount of immune infiltrates expressing high levels of TNFR and IL-20 subfamily cytokines congregate within the inflamed disease tissues. Colocalization experiments reveal that signals from IL-20R2 and TNF transduction pathways seem to converge in macrophages and function in tandem in orchestrating the pathogenesis of RA. Elucidation of this interaction provides a better understanding of cytokine cross-talk in RA and a rationale for more effective biologic therapies that target IL-20R2 instead of individual cytokines from IL-20 family.
Department of Biochemistry and Molecular Biology, School of Life Sciences, Sichuan University, Chengdu 610000, China.
Xinyu
X
Liu
Department of Biochemistry and Molecular Biology, School of Life Sciences, Sichuan University, Chengdu 610000, China.
Hong
0000-0001-7212-457X
H
Zhou
Department of Biochemistry and Molecular Biology, School of Life Sciences, Sichuan University, Chengdu 610000, China.
Xueqin
X
Huang
Department of Biochemistry and Molecular Biology, School of Life Sciences, Sichuan University, Chengdu 610000, China.
Jingjing
J
Cui
Department of Biochemistry and Molecular Biology, School of Life Sciences, Sichuan University, Chengdu 610000, China.
Tianzhen
T
Long
Department of Biochemistry and Molecular Biology, School of Life Sciences, Sichuan University, Chengdu 610000, China.
Yang
Y
Xu
Department of Biochemistry and Molecular Biology, School of Life Sciences, Sichuan University, Chengdu 610000, China.
Haipeng
H
Liu
Department of Biochemistry and Molecular Biology, School of Life Sciences, Sichuan University, Chengdu 610000, China.
Ruoxuan
0000-0002-0851-1556
R
Yu
Department of Biochemistry and Molecular Biology, School of Life Sciences, Sichuan University, Chengdu 610000, China.
Rongchuan
0000-0001-6198-8612
R
Zhao
Laboratory for Gene and Cell Therapy, Sichuan University, Chengdu 610041, China.
Guangping
0000-0002-7348-5526
G
Luo
Laboratory for Gene and Cell Therapy, Sichuan University, Chengdu 610041, China.
Anliang
A
Huang
Clover Biopharmaceuticals, Chengdu 610041, China; and.
Joshua G
JG
Liang
Department of Biochemistry and Molecular Biology, School of Life Sciences, Sichuan University, Chengdu 610000, China; liangpeng@scu.edu.cn liang.peng@cloverbiopharma.com.|Laboratory for Gene and Cell Therapy, Sichuan University, Chengdu 610041, China.|Clover Biopharmaceuticals, Chengdu 610041, China; and.|GenHunter Corporation, Nashville, TN 37211.
Peng
P
Liang
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000276:immunology / Q000628:therapy*; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000628:therapy*; D002460:Cell Line; D049109:Cell Proliferation; D016207:Cytokines / Q000037:antagonists & inhibitors; D000068800:Etanercept / Q000627:therapeutic use; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics; D007167:Immunotherapy / Q000379:methods*; D016753:Interleukin-10 / Q000037:antagonists & inhibitors; D007378:Interleukins / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D011485:Protein Binding; D015202:Protein Engineering; D018123:Receptors, Interleukin / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000627:therapeutic use*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D000099180:Interleukin-24
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D000068800:Etanercept; D007141:Immunoglobulin Fc Fragments; D016753:Interleukin-10; D007378:Interleukins; D018123:Receptors, Interleukin; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; C498891:Il19 protein, mouse; C431904:Il24 protein, mouse; D000099180:Interleukin-24; C494086:STAT3 protein, human; C492510:interleukin-20 receptor; C422042:interleukin 20