Unknown,Transcriptomics,Genomics,Proteomics

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Inhibition of dendritic cell maturation and effector function

ABSTRACT: The initiation of donor derived dendritic cell (DC) adhesion and migration are one of the key events mediated by ischemia reperfusion injury (IRI) following solid organ transplantation. Recently we have been able to demonstrate that a single donor treatment with the synthetic metalloporphyrin cobalt protoporphyrin (CoPPIX) for heme oxygenase 1 (HO-1) induction results in the reduction of donor-derived DCs following IRI thus leading to the preservation of graft long-term function. Gene expression analysis in murine liver revealed the up-regulation of the signal transducer and activator of transcription 3 (STAT3) after CoPPIX treatment. Since it has been shown that CoPPIX is able to inhibit DC maturation, we could demonstrate that DC (-LPS) induced maturation guided by the secretion of pro-inflammatory cytokines and alloreactive T cell proliferation is dependent of STAT3 phosphorylation and independent of HO-1 activity. These observations highlight the immunomodulatory capacity of STAT3 which might be of further interest for the inhibition of immune response. Keywords: dendritic cells, heme oxygenase-1 (HO-1), STAT3, cobalt protoporphyrin For the analysis of gene expression profiles in vivo C57BL/6 mice were treated either with 5 mg/kg CoPPIX, i.p., 50 mg/kg MC, p.o. and 500 ppm CO for 6 or 24 hrs (3 animals in each group). Untreated C57BL/6 mice were used as controls (n=9). After 6 or 24 hrs of treatment animals were sacrificed and whole livers were harvested for analysis.

ORGANISM(S): Mus musculus

SUBMITTER: JÃ³zef Dulak

PROVIDER: E-GEOD-8452 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Inhibition of dendritic cell maturation and function is independent of heme oxygenase 1 but requires the activation of STAT3.

Mashreghi Mir-Farzin MF Klemz Roman R Knosalla Isabela Schmitt IS Gerstmayer Bernhard B Janssen Uwe U Buelow Roland R Jozkowicz Alicja A Dulak Jozef J Volk Hans-Dieter HD Kotsch Katja K

Journal of immunology (Baltimore, Md. : 1950) 20080601 12

The induction of heme oxygenase 1 (HO-1) by a single treatment with cobalt protoporphyrin (CoPPIX) protects against inflammatory liver failure and ischemia reperfusion injury after allotransplantation. In this context, the HO-1-mediated inhibition of donor-derived dendritic cell maturation and migration is discussed as one of the key events of graft protection. To investigate the poorly understood mechanism of CoPPIX-induced HO-1 activity in more detail, we performed gene expression analysis in ...[more]

PMID: 18523255

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Project description:Dendritic cells (DC) play a vital role in the induction of activation or tolerance of immune response. STAT3 is a master transcriptional regulator of immune response in DCs by positively or negatively regulating DC function, but the mechanisms are unknown. STAT3 is post-translationally modified by acetylation or phosphorylation. While much is understood about transcriptional targets of phosphorylated STAT3, the gene targets and the functional impact of acetylated-STAT3 remain unclear. We aimed to answer the gene targets of acetylated-STAT3 and test the hypothesis that acetylation of STAT3 plays a key role in negative regulation of DCs. We performed genome-wide binding analysis of acetyl-STAT3 by ChIP-Seq coupled with gene expression microarrays. Acetylation of STAT3 induced by SAHA increased its capability to bind to target DNA sites in genome. Theses binding sites were mostly proximal but some were also distal up to over 100 kb from transcription start site. Gene expression array showed 1701 genes up-regulated and 1668 genes down-regulated. Proximal binding of acety-STAT3 showed more effective transcription function than distal binding. In top 500 binding peaks, the frequency of canonical motifs bound by acetyl-STAT3 were significantly higher than that for noncanonical motifs (p<0.00001). Functional analysis revealed that acetyl-STAT3 regulates target genes by upregulating genes that are primarily involved in negative regulation of cytokine production and IL-10 signaling, or downregulating genes that are primarily involved in immune effector process and antigen processing/presentation. Upregulation of IL-10Ra by acetyl-STAT3 contributes to the enhanced sensitivity of IL-10 signaling and negative regulation of DC function. Bone marrow derived dendritic cells were treated with SAHA (500 nm) or diluent for 12 hours. ChIP was performed using antibodies against STAT3, H3K4me3 and matched IgG control. DNA binding profiles were generated by deep sequencing using Illumina HiSeq 2000.

Dataset Information

Inhibition of dendritic cell maturation and effector function

Publications

Inhibition of dendritic cell maturation and function is independent of heme oxygenase 1 but requires the activation of STAT3.

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