title: Roles of Ras and extracellular signal-regulated kinase-dependent IkappaBalpha degradation in oridonin-enhanced phagocytosis of apoptotic cells by human macrophage-like U937 cells.
abstract: Rapid recognition and ingestion of apoptotic cells by phagocytes are important for the prevention of toxic intracellular contents release, thereby attenuate inflammation and autoimmune diseases such as systemic lupus erythematosus (SLE). We have reported that oridonin isolated from Rabdosia rubescens enhanced phagocytosis of apoptotic U937 cells by macrophage-like U937 cells through TNFalpha and IL-1beta release. In this study, the molecular mechanisms involved in this phagocytic process are investigated. Inhibitors of Ras and Raf1 kinase significantly reduced oridonin-induced phagocytic stimulation as well as extracellular signal-regulated kinase (ERK) phosphorylation. Simultaneously, oridonin-enhanced engulfment was partially blocked by a nuclear factor (NF)-kappaB inhibitor PDTC or proteasome inhibitor MG132. Further studies revealed that oridonin induced IkappaBalpha degradation, which was prevented by Ras inhibitor manumycin A, ERK inhibitor PD98059, but not prevented by c-Jun N-terminal kinase (JNK) MAPK inhibitor SP600125, and up-regulated expression of IL-1beta precursor. These results demonstrate that Ras/Raf1/ERK signaling pathway-dependent IkappaBalpha degradation, resulting in NF-kappaB activation, participates in regulation of oridonin-enhanced phagocytosis, and one of its effector functions is to induce synthesis of IL-1beta, which partially contribute to phagocytic activity of oridonin.
authors.affiliation: China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Parmaceutical University, 103 Wenhua Road, Shenyang, Liaoning Province, 110016, PR China.
authors.forename: Yan Qiu
authors.initials: YQ
authors.lastname: Liu
authors.forename: Song
authors.initials: S
authors.lastname: You
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Tashiro
authors.forename: Satoshi
authors.initials: S
authors.lastname: Onodera
authors.forename: Takashi
authors.initials: T
authors.lastname: Ikejima
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D004224:Diterpenes / Q000494:pharmacology*; D045786:Diterpenes, Kaurane; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D005434:Flow Cytometry; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D020672:I-kappa B Proteins / Q000502:physiology*; D007375:Interleukin-1 / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology; D010587:Phagocytosis / Q000187:drug effects*; D011090:Polyenes / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors; D013859:Thiocarbamates / Q000494:pharmacology; D020298:U937 Cells; D018631:ras Proteins / Q000037:antagonists & inhibitors
chemical_list: D004224:Diterpenes; D045786:Diterpenes, Kaurane; D020672:I-kappa B Proteins; D007375:Interleukin-1; D007976:Leupeptins; D011090:Polyenes; D053284:Polyunsaturated Alkamides; D013859:Thiocarbamates; C011959:oridonin; C066229:prolinedithiocarbamate; D011392:Proline; D019908:Proto-Oncogene Proteins c-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins; C054474:manumycin; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde