Abstract
Ampelopsis brevipedunculata (Maxim.) Trautv. (AB), a traditional East Asian medicine, exhibits protective effects against several inflammatory diseases. Our search for an inhibitor of IL-6-induced JAK2/STAT3 activation revealed that AB ethanolic extract (ABE) had a significant inhibitory effect on IL-6-induced STAT3 expression in Hep3B cells. The isolation and purification of an EtOAc-soluble fraction of ABE (ABEA) using reversed-phase high-performance liquid chromatography (RP-HPLC) afforded 17 compounds. The structures of these compounds (1-17) were elucidated based on 1H and 13C nuclear magnetic resonance (NMR) spectroscopy as well as electrospray-ionization mass spectrometry (ESI-MS) data. ABE and ABEA were screened by a luciferase assay using Hep3B cells transfected with the STAT3 reporter gene. ABEA exhibited potent inhibitory effects on IL-6-induced STAT3 expression; moreover, these effects arose from the inhibition of the phosphorylation of the STAT3, JAK2, and ERK proteins in U266 cells. In addition, the compounds isolated from ABEA were measured for their inhibitory effects on IL-6-stimulated STAT3 expression. Of the compounds isolated, betulin showed the greatest inhibitory effects on IL-6-induced STAT3 activation in the luciferase assay (IC50 value: 3.12 μM). Because of its potential for inhibiting STAT3 activation, A. brevipedunculata could be considered a source of compounds of pharmaceutical interest.
Highlights
Interleukin 6 (IL-6), which is involved in various physiological functions including neurodevelopment, haematopoiesis, bone metabolism, and immunity [1,2,3,4], is implicated in many inflammatory diseases, such as asthma, arthritis, osteoporosis, diabetes, cancer, ulcerative colitis, and Crohn’s disease, and plays an important role in inflammation and immune diseases [5,6,7]
signal transducer and activator of transcription 3 (STAT3) is a member of the STAT family of proteins, and STAT3 plays a role in the response to growth factors and cytokines such as IL-6 [8]
STAT3 is phosphorylated by receptor-associated JAK2 to form homo- or heterodimers and translocates to the nucleus where it acts as a transcription activator [9]
Summary
Interleukin 6 (IL-6), which is involved in various physiological functions including neurodevelopment, haematopoiesis, bone metabolism, and immunity [1,2,3,4], is implicated in many inflammatory diseases, such as asthma, arthritis, osteoporosis, diabetes, cancer, ulcerative colitis, and Crohn’s disease, and plays an important role in inflammation and immune diseases [5,6,7]. STAT3 is phosphorylated by receptor-associated JAK2 to form homo- or heterodimers and translocates to the nucleus where it acts as a transcription activator [9]. JAK2 provides “instructions” for producing proteins that promote the growth, development, and proliferation of cells and mediates essential signalling events involved in both innate and adaptive immunity. The JAK2/STAT signalling pathways is very important for cell growth and differentiation, and natural products that target JAK2/STAT have potential for the treatment of cancer and tumours [11]
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