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A Novel Small-Molecule Inhibitor Targeting the IL-6 Receptor beta Subunit, Glycoprotein 130

Authors
Hong, Soon-SunChoi, Jung HoLee, Sung YoonPark, Yeon-HwaPark, Kyung-YeonLee, Joo YoungKim, JuyoungGajulapati, VeeraswamyGoo, Ja-IlSingh, SarbjitLee, KyeongKim, Young-KookIm, So HeeAhn, Sung-HoonRose-John, StefanHeo, Tae-HweChoi, Yongseok
Issue Date
1-7월-2015
Publisher
AMER ASSOC IMMUNOLOGISTS
Citation
JOURNAL OF IMMUNOLOGY, v.195, no.1, pp.237 - 245
Indexed
SCIE
SCOPUS
Journal Title
JOURNAL OF IMMUNOLOGY
Volume
195
Number
1
Start Page
237
End Page
245
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/93047
DOI
10.4049/jimmunol.1402908
ISSN
0022-1767
Abstract
IL-6 is a major causative factor of inflammatory disease. Although IL-6 and its signaling pathways are promising targets, orally available small-molecule drugs specific for IL-6 have not been developed. To discover IL-6 antagonists, we screened our in-house chemical library and identified-LMT-28, a novel synthetic compound, as a candidate IL-6 blocker. The activity, mechanism of action, and direct molecular target of LMT-28 were investigated. A reporter gene assay showed that LMT-28 suppressed activation of STAT3 induced by IL-6, but not activation induced by leukemia inhibitory factor. In addition, LMT-28 downregulated IL-6-stimulated phosphorylation of STAT3, gp130, and JAK2 protein and substantially inhibited IL-6-dependent TF-1 cell proliferation. LMT-28 antagonized IL-6-induced TNF-alpha production in vivo. In pathologic models, oral administration of LMT-28 alleviated collagen-induced arthritis and acute pancreatitis in mice. Based on the observation of upstream IL-6 signal inhibition by LMT-28, we hypothesized IL-6, IL-6R alpha, or gp130 to be putative molecular targets. We subsequently demonstrated direct interaction of LMT-28 with gp130 and specific reduction of IL-6/IL-6R alpha complex binding to gp130 in the presence of LMT-28, which was measured by surface plasmon resonance analysis. Taken together, our data suggest that LMT-28 is a novel synthetic IL-6 inhibitor that functions through direct binding to gp130.
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생명과학대학 (생명공학부)
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