title: Altered MARCH1 ubiquination-regulated dendritic cell immune functions during the early stage of zymosan-induced multiple organ dysfunction syndrome (MODS) in mice.
abstract: Using a zymosan-induced mouse model of multiple organ dysfunction syndrome (MODS), we previously found profound increases in spleen immune cells' expressions of ubiquitin and MHC-II molecules and increased CD11c+ dendritic cells (DCs) within 24h of zymosan injection. We postulated that the early stage of MODS altered DCs function via an ubiquitination-associated mechanism. We intraperitoneally injected zymosan into 100 male C57BL/6 mice (0.8mg/g) and randomly divided them into 5 groups based on the days after injection (20mice/group): 1d, 3d, 5d, 7d, and 10d. Mice were examined for spleen CD11c+ DC functions at the indicated days. Untreated mice were used for normal spleen tissue and T cell samples. By qPCR, IL-12 and TNF-α mRNA expressions in spleen CD11c+ DCs were significantly increased in MODS 1d mice; on subsequent days post-injection, these mRNA levels gradually returned to control levels. The same patterns were found for MODS mice DCs induction of untreated mouse T cells proliferation and IL-2 and IFN-γ mRNA expressions. When T cell functions were examined using MODS 1d DCs with and without MG132 treatment, an inhibitor of ubiquitinated protein degradation, T cell functional activities were enhanced by DCs treated with MG132. MODS 1d DCs also had significantly reduced MARCH1 mRNA expression, a key ubiquitin ligase that regulates DCs MHC-II expression. Silencing DCs MARCH1 expression with siRNA resulted in enhancing their induction of T cell functional activities. Using co-immunoprecipitation, Western blot, and flow cytometry assays, we deduced that MARCH1 ubiquitinated DC surface MHC-II molecules to regulate DC's immune functions in MODS mice. Our results suggest that aberrant degradation of spleen DCs MARCH1-mediated ubiquitinated proteins is involved during the earliest stage of MODS development.
authors.affiliation: Department of Dermatology, The Air Force General Hospital of PLA, Beijing 100142, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.forename: Jiang-yang
authors.initials: JY
authors.lastname: Lu
authors.forename: Qian
authors.initials: Q
authors.lastname: Liu
authors.forename: Hong-wei
authors.initials: HW
authors.lastname: Wang
authors.forename: Huiqin
authors.initials: H
authors.lastname: Guo
mesh_terms: D000818:Animals; D039521:CD11c Antigen / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D015870:Gene Expression; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D009102:Multiple Organ Failure / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D034622:RNA Interference; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D015054:Zymosan / Q000009:adverse effects
chemical_list: D039521:CD11c Antigen; D000949:Histocompatibility Antigens Class II; D015054:Zymosan; C545340:MARCH1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex