TY - JOUR
T1 - A novel small-molecule inhibitor targeting the IL-6 receptor β subunit, glycoprotein 130
AU - Hong, Soon Sun
AU - Choi, Jung Ho
AU - Lee, Sung Yoon
AU - Park, Yeon Hwa
AU - Park, Kyung Yeon
AU - Lee, Joo Young
AU - Kim, Juyoung
AU - Gajulapati, Veeraswamy
AU - Goo, Ja Il
AU - Singh, Sarbjit
AU - Lee, Kyeong
AU - Kim, Young Kook
AU - Im, So Hee
AU - Ahn, Sung Hoon
AU - Rose-John, Stefan
AU - Heo, Tae Hwe
AU - Choi, Yongseok
N1 - Publisher Copyright:
© 2015 by The American Association of Immunologists, Inc.
PY - 2015/7/1
Y1 - 2015/7/1
N2 - 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 identifiedLMT-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-α 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-6Rα, or gp130 to be putative molecular targets. We subsequently demonstrated direct interaction of LMT-28 with gp130 and specific reduction of IL-6/IL-6Rα 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.
AB - 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 identifiedLMT-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-α 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-6Rα, or gp130 to be putative molecular targets. We subsequently demonstrated direct interaction of LMT-28 with gp130 and specific reduction of IL-6/IL-6Rα 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.
UR - http://www.scopus.com/inward/record.url?scp=84932163442&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1402908
DO - 10.4049/jimmunol.1402908
M3 - Article
C2 - 26026064
AN - SCOPUS:84932163442
SN - 0022-1767
VL - 195
SP - 237
EP - 245
JO - Journal of Immunology
JF - Journal of Immunology
IS - 1
ER -