A novel tylophorine analog NK-007 ameliorates colitis through inhibition of innate immune response |
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| Institution: | 1. Natural Resource Ecology Laboratory, Colorado State University, 200 West Lake Street, Fort Collins, CO 80523-1499, USA;2. National Renewable Energy Laboratory, 15013 Denver West Parkway, Golden, CO 80401-3305, USA;3. MicroChem Technologies Inc., 8999 W. Harvard Pl., Lakewood, CO 80227-6106, USA;4. Biology Department, Bradley University, 1501 W. Bradley Avenue, Peoria, IL 61625, USA;5. USDA ARS, Cent Great Plains Res Stn, Akron, CO 80720, USA;6. Department of Soil and Crop Sciences, Colorado State University, 200 West Lake Street, Fort Collins, CO 80523-1499, USA;1. State Key Laboratory of Water Environment Simulation, School of Environment, Beijing Normal University, Beijing 100875, China;2. State Key Laboratory of Environmental Criteria and Risk Assessment, Chinese Research Academy of Environmental Sciences, Beijing 100012, China;3. Stockbridge School of Agriculture, University of Massachusetts, Amherst, MA 01003, USA |
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| Abstract: | In this study, we synthesized (±)-tylophorine malate (NK-007), an analog of tylophorine (DCB3503), and analyzed its anti-inflammatory effect in vivo using a dextran sulfate sodium (DSS)-induced colitis model and an acetic acid-induced colitis model. As indicated by disease activity index (DAI) and degree of macroscopic colonic damage, NK-007 can significantly suppress colitis. To delineate the underlying mechanism, we have explored the influence of NK-007 on the production of TNF-α by murine primary bone marrow-derived dendritic cells (BMDCs) as well as monocyte/macrophage cell line Raw 264.7 triggered by lipopolysaccharide (LPS). For both types of innate immune cells, NK-007 showed a potent TNF-α inhibitory effect, and has in addition reduced the expression of IL-12 in BMDCs. Moreover, Raw cells treated with NK-007 also showed decreased phosphorylation of NF-κB, which may explain the protective immune-regulatory effect of NK-007 for experimental colitis. |
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