title: SHARPIN is essential for cytokine production, NF-κB signaling, and induction of Th1 differentiation by dendritic cells.
abstract: Spontaneous mutations of the Sharpin (SHANK-associated RH domain-interacting protein, other aliases: Rbckl1, Sipl1) gene in mice result in systemic inflammation that is characterized by chronic proliferative dermatitis and dysregulated secretion of T helper1 (Th1) and Th2 cytokines. The cellular and molecular mechanisms underlying this inflammatory phenotype remain elusive. Dendritic cells may contribute to the initiation and progression of the phenotype of SHARPIN-deficient mice because of their pivotal role in innate and adaptive immunity. Here we show by flow cytometry that SHARPIN- deficiency did not alter the distribution of different DC subtypes in the spleen. In response to TOLL-like receptor (TLR) agonists LPS and poly I:C, cultured bone marrow-derived dendritic cells (BMDC) from WT and mutant mice exhibited similar increases in expression of co-stimulatory molecules CD40, CD80, and CD86. However, stimulated SHARPIN-deficient BMDC had reduced transcription and secretion of pro-inflammatory mediators IL6, IL12P70, GMCSF, and nitric oxide. Mutant BMDC had defective activation of NF-κB signaling, whereas the MAPK1/3 (ERK1/2) and MAPK11/12/13/14 (p38 MAP kinase isoforms) and TBK1 signaling pathways were intact. A mixed lymphocyte reaction showed that mutant BMDC only induced a weak Th1 immune response but stimulated increased Th2 cytokine production from allogeneic naïve CD4(+) T cells. In conclusion, loss of Sharpin in mice significantly affects the immune function of DC and this may partially account for the systemic inflammation and Th2-biased immune response.
authors.affiliation: Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana, United States of America.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
authors.forename: Anna
authors.initials: A
authors.lastname: Sokolovska
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Seymour
authors.forename: John P
authors.initials: JP
authors.lastname: Sundberg
authors.forename: Harm
authors.initials: H
authors.lastname: Hogenesch
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis*; D003713:Dendritic Cells / Q000276:immunology*; D007109:Immunity; D007249:Inflammation; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D018417:Th1 Cells / Q000166:cytology* / Q000276:immunology
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C554944:Sipl1 protein, mouse