| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Improved Shigella Vaccine
|
DC Function after Trauma-Hemorrhage
Loss of splenic dendritic cells (DCs) occurs in patients with hemorrhage following traumatic injury and may contribute to the susceptibility of those patients to sepsis. But the functional capabilities of the residual splenic DCs have not been determined. Kawasaki et al. (p. 4514
) found that plasma levels of TNF-
, IL-6, MCP-1, and IL-10 were significantly increased in mice subjected to trauma (laparotomy) and hemorrhage compared with sham-operated animals. Splenic DCs positive for annexin V, that also did or did not stain with propidium iodide, increased in number in trauma-hemorrhage mice. Surface levels of MHC class II and CD83 molecules were significantly decreased on viable splenic DCs from the trauma-hemorrhage animals, and CD11c+ spleen cells from the trauma-hemorrhage mice had reduced capacity for stimulating T cell proliferation in vitro. Less TNF-, IL-6, IFN-
, IL-12p40, and IL-12p70 were produced by LPS stimulation of splenic DCs from trauma-hemorrhage mice vs controls. The loss of splenic DCs and down-regulation of maturation Ags on residual splenic DCs suggests that suppression of splenic DC maturation leads to an impaired ability of mice to eliminate infectious agents after trauma-hemorrhage.
IFNing with the STATus Quo
The potent antiviral protein A3G (APOBEC3G = apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G) is induced by IFNs and is effective against retroviruses and hepatitis B virus. However, details regarding its transcriptional regulation are not available. Sarkis et al. (p. 4530
) detected by RT-PCR and immunoblotting wide individual variations of A3G transcription and translation in response to treatment of primary human hepatocytes and macrophages with IFN- or IFN-; no A3G up-regulation was seen in primary CD4+ T cells. Pretreatment of liver cells with Rotterlin prevented induction of A3G but not other IFN--responsive genes. IFN--induced A3G transcription in a hepatocyte cell line was prevented by a transfected short interfering RNA specific for STAT2 or IFN regulatory factor-9, but not for STAT1 or PKC-
, or by a general inhibitor of JAKs; inhibition of JAKs or a short interfering RNA specific for STAT1, but not for STAT2, blocked IFN--induced A3G induction. The experiments demonstrate the existence of a STAT1-independent, but STAT2-dependent, pathway for IFN--stimulated up-regulation of antiviral A3G unique to the human hepatocyte.
In the (CD1d) Groove
|
Complex(ity) of Fc
RI Transcription
|
- and -chains of high-affinity FcRI transmit intracellular signals resulting from binding of IgE to the -chain. Since expression of the -chain is limited to mast cells and basophils, a better understanding of its transcriptional regulation would be useful in developing therapies that target it in allergy and asthma. The Ra laboratory described repression of human -chain gene expression via binding of myeloid zinc finger (MZF-1) transcription factor to a DNA element in the fourth intron. They identified a second factor, four-and-a-half-LIM domain protein (FHL3), in a large nuclear complex with MZF-1. In a continuation of their studies, Takahashi et al. (p. 4605
) used a three-hybrid screen of a human cDNA expression library to identify a third factor, nuclear factor Y (NFY), which interacted through its C subunit with the MZF-1/FHL3 complex. In vitro-transcribed/translated tagged MZF-1 and NFY-C were coimmunoprecipitated in the presence of FHL3 but not in its absence. Chromatin immunoprecipitation assays using anti-NFY-C Ab confirmed that NFY-C associated with the MZF-1 element in the fourth intron of the -chain gene. Additionally, Abs against histone deacetylases 1 or 2, known to bind to the A subunit of NFY, were shown by chromatin immunoprecipitation assays to be associated with the MZF-1 element. Anti-acetylated histone H3 and anti-acetylated histone H4 Abs demonstrated that treatment of a human mast cell line with GM-CSF for 4 or 10 days reduced histone acetylation within the fourth intron of the -chain gene and decreased -chain mRNA expression. No decrease in acetylation was noted in a cell overexpressing a MZF-1 mutant deleted in its FHL3-interacting region. The authors propose that expression of the -chain of human FcRI is regulated through a MZF-1/FHL3/NFY complex and that GM-CSF suppresses expression by recruitment of histone deacetylases. Blocking CIITA Gene Transcription
Expression of MHC CIITA is constitutive in bone marrow-derived APCs but requires IFN- for induction in cells at inflammatory sites. B lymphocyte-induced maturation protein-1 (PRDM1/Blimp-1) binds to promoter IV (pIV)of the CIITA gene to prevent CIITA-mediated transcription of the MHC class II gene in a variety of cells. However, the mechanism of PRDM1 repression is not known. Tooze et al. (p. 4584
) confirmed binding of PRDM1 with CIITA-pIV by chromatin immunoprecipitation and EMSAs on lysates of human myeloma cells that have high levels of PRDM1. Cotransfection of HeLa cells with a CIITA-pIV expression plasmid prevented IFN- stimulation of a luciferase reporter carrying the CIITA-pIV promoter with its embedded IFN regulatory factor (IRF)-E site. Addition of lysates containing PRDM1 decreased binding of IRF-1 or IRF-2 to CIITA-pIV in extracts of cells transfected with vectors expressing the IRFs; a complex consistent with PRDM1 binding alone was detected. Mutation of aa 3 and aa 9 of the IRF-E binding site reduced binding of PRDM1, but not IRF-1 or IRF-2, compared with the wild-type IRF-E sequence as determined by EMSA and IFN--mediated induction of luciferase activity. Introduction of a short interfering PRDM1 mRNA into human myeloma cells led to a 5-fold increase in CIITA-pIV expression as determined by chromatin immunoprecipitation. In the model presented by the authors, PRDM1 represses MHC class II expression by competing with IRF-1 and IRF-2 for occupancy at the IRF-E binding site within the CIITA-pIV promoter following IFN- stimulation of human cells.
Complementing I/R Injury
|
Summaries written by Dorothy L. Buchhagen, Ph.D.
Related articles in The JI:
Induction of Class II Transactivator: A Role for PRDM1/Blimp-1 in Regulation of Cytokine Signaling
-Chain Gene Induced by GM-CSF
| ||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
