MS80, a novel sulfated polysaccharide, inhibits CD40-NF-kappaB pathway via targeting RIP2.
In the previous studies, MS80 was found to be able to inhibit the pulmonary fibrosis. However, the target of MS80 remains unclear. To determine the target and the antifibrosis mechanisms of MS80, affinity column, MALDITOF-MS/MS, co-immunoprecipitation, and co-localization were used. The results showed that MS80 targeting protein was receptor interacting protein 2 (RIP2), which was further confirmed by co-immunoprecipitation and co-localization. Moreover, MS80 inhibited the CD40 ligation-induced NF-kappaB activation, and subsequently inflammatory cytokines secretion, the collagen synthesis, and the excessive proliferation of fibroblasts. Thus the detailed molecular machinery was ascribed to the involvement of MS80 in targeting CD40 signal pathway via binding and blocking RIP2, the key component of CD40 signal transduction. The findings addressed here may substantially account for the effects of MS80 in combating the pulmonary fibrosis.
Du
Xiaoguang
X
Department of Molecular Pharmacology, School of Medicine and Pharmacy, Ocean University of China, Qingdao, People's Republic of China.
Jiang
Shan
S
Liu
Hongchun
H
Xin
Xianliang
X
Li
Jing
J
Geng
Meiyu
M
Jiang
Handong
H
D000595:Amino Acid Sequence; D019013:CD40 Antigens / Q000378:metabolism / Q000502:physiology*; D023201:CD40 Ligand / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D016503:Drug Delivery Systems; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D046911:Macromolecular Substances / Q000737:chemistry; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D009844:Oligosaccharides / Q000008:administration & dosage / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013431:Sulfates / Q000378:metabolism
D019013:CD40 Antigens; C545090:MS80 oligosaccharide; D046911:Macromolecular Substances; D016328:NF-kappa B; D009844:Oligosaccharides; D013431:Sulfates; D023201:CD40 Ligand; C506253:RIPK2 protein, human; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2