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Eur J Pharmacol. 2018 Mar 15;823:1-10. doi: 10.1016/j.ejphar.2018.01.037. Epub 2018 Feb 4.

JN-2, a C-X-C motif chemokine receptor 3 antagonist, ameliorates arthritis progression in an animal model.

Author information

1
Department of Cell and Developmental Biology, Dental Research Institute, School of Dentistry, Seoul National University, Seoul 110-749, Republic of Korea.
2
The University of Texas MD Anderson Cancer Center, Department of Neuro-Oncology, Huston, TX, 77030, USA.
3
Clinical Research Division, Korea Institute of Oriental Medicine, 483 Expo-Ro, Yuseong-Gu, Daejeon 305-811, Republic of Korea. Electronic address: hyunil74@kiom.re.kr.
4
Department of Cell and Developmental Biology, Dental Research Institute, School of Dentistry, Seoul National University, Seoul 110-749, Republic of Korea. Electronic address: zang1959@snu.ac.kr.

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease that is characterized by uncontrolled joint inflammation and destruction of bone and cartilage. Previous studies have shown that C-X-C motif chemokine 10 (CXCL10) has important roles in RA development and that blocking CXCL10 expression effectively inhibits arthritis progression in animal models. However, clinical study using anti-CXCL10 monoclonal antibody (MDX-1100) to block CXCL10 expression in patients with RA did not show significant effectiveness. Therefore, we turned our attention to C-X-C motif chemokine receptor 3 (CXCR3), which is a receptor for CXCL9, CXCL10, and CXCL11, to treat RA. In the present study, administration of JN-2, our newly developed CXCR3 antagonist, ameliorated the progression of arthritis in a collagen-induced arthritis animal model. JN-2 also inhibited CXCR3-induced cell migration and pro-inflammatory cytokine expression of bone marrow-derived macrophages and CD4+ T cells in vitro. In addition, we found that CXCL10 formed an auto-amplification loop through activation of NFκB. Furthermore, Phosphorylation of p65 at serine 536 played an important role in the auto-amplification of CXCL10. Overall, the present results demonstrated that JN-2 decreased inflammation by inhibiting CXCR3-enhanced cell migration and pro-inflammatory cytokine expression, which then ameliorated arthritis progression.

KEYWORDS:

CXCL10; CXCR3; Collagen-induced arthritis; Inflammation; Rheumatoid arthritis

PMID:
29378189
DOI:
10.1016/j.ejphar.2018.01.037
[Indexed for MEDLINE]

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