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PGE2/EP4 in the Zebrafish Thymus
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Wilms’ Tumor 1 (WT1) is an MMP-9 Gene Repressor
Matrix metalloproteinase-9 (MMP-9) expression is increased in lung epithelial cells (LECs) in several lung conditions, including asthma, and in the blood of affected patients. Although NO is known to regulate MMP-9 through a soluble guanylate cyclase (sGC)-dependent pathway, details at the transcriptional level are lacking. Marcet-Palacios et al. (p. 256 ) measured increased NO, inducible NO synthase (iNOS) protein and mRNA, and MMP-9 mRNA in human LECs treated with TNF. Inhibitors of iNOS activity blocked only MMP-9 mRNA expression and MMP-9 activity in cell supernatants. Inhibitors of sGC or cAMP-dependent protein kinase A also reduced MMP-9 activity. In silico analysis identified a conserved CA repetitive element with binding sites for the WT1 transcriptional repressor in the 5' region of the MMP-9 gene from several species. All human LECs expressed WT1 mRNA and protein as determined by RT-PCR and immunoblot analyses, respectively, with nuclear and perinuclear localization visualized by immunohistochemistry. The WT1 protein was immunoprecipitated from human LEC lysates using a complex containing the WT1 region of the MMP-9 promoter. Treatment of cells with TNF did not affect WT1 mRNA levels but caused WT1 protein translocation from the nucleus to the cytosol; the iNOS inhibitor prevented the translocation. A WT1-specific short interfering RNA reversed the iNOS inhibitor blockade of TNF-induced, up-regulated MMP-9 ex-pression. The experiments demonstrate that WT1 represses MMP-9 gene expression in human LECs in a pathway regulated by NO.
Hiding Out and Alive in the Liver
Effector CD8+ T cells that accumulate in the liver during infections of mice with hepatotropic viruses are thought to be dysfunctional and apoptotic. On p. 201
, Polakos et al. confirmed their previous finding of greater virus-specific CD8+ T cell accumulation in the liver compared with the lung early during primary or secondary influenza virus infection of mice. Neither infectious virus nor viral Ag was detected in homogenates of livers from infected animals. Similarly, adoptively transferred activated OVA peptide-specific CD8+ T cells accumulated almost exclusively in recipient livers compared with naive CD8+ T cells that distributed equally among lymphoid tissues and livers. T cells from the livers of virus-infected mice produced IFN-
when stimulated with viral peptide ex vivo and lysed target cells pulsed with viral peptide both ex vivo and in vivo. The proportion of apoptotic CD8+ T cells in livers of infected animals decreased throughout virus infection. Splenic or liver OVA-TCR-transgenic CD8+ T cells activated by OVA peptide in vivo homed preferentially to the livers of recipient mice and divided in vivo in response to OVA peptide inoculation of the recipients at 8 or 45 days after adoptive transfer. Donor CD8+ T cells from livers of virus-infected mice transplanted into naive recipients were recovered in recipient spleens 50 days posttransplant and responded in vivo to influenza virus infection. The experiments show that viral Ag-free livers of virus-infected mice are reservoirs of long-lived, functional influenza virus-specific CD8+ T cells.
Toponome of Inflammatory Bowel Disease
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B expression compared with UC and control tissues; UC tissues have more apoptotic CD4+ T cells that are NF-B, PARP, and caspase-8 positive. Anticolocalization analysis determined that NF-B-positive cells in CD and UC tissues lacked p53. MELC also showed an increase in naive T cells in CD tissues. CD could be distinguished from UC by using PARP-2 as a base motif in hub analyses. Regulatory CD4+CD25+ T (Treg) cells were elevated preferentially in UC tissues. CD7– Treg cells, which have increased attachment to vascular endothelial cells during chronic inflammation and coexpress the 
2 integrin, were more numerous in CD and UC tissues compared with controls, whereas there were more cells coexpressing the 
L integrin only in UC. HLA-DR-positive Treg cells were significantly increased in CD and moderately increased in UC compared with healthy tissues. This use of the novel MELC technology provides context-dependent protein information of the inflamed intestinal mucosa that distinguishes two IBDs, CD and UC. Muscling in on DNA Vaccines
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ex vivo. Similar results were obtained using muscle cells transfected with pOVA in vitro, but not with OT-1 or untransfected muscle cells exposed to free OVA. pOVA-transfected mouse and human muscle cells up-regulated expression of MHC class I and the B7.1 or BB-1 costimulatory molecule, respectively, as determined by flow cytometry, RT-PCR, and immunohistochemistry. Histological examination of the muscle vaccination site from mice indicated a substantial influx of large numbers of CD8+ T cells by day 5 after i.m. vaccination. Mouse and muscle cells transfected with pOVA or empty vector increased mRNA expression of several genes involved in Ag processing and presentation as well as cytokines and chemokines. Surprisingly, mouse cells transfected with empty vector were able to present an OVA peptide to OT-1 cells. Short interfering RNAs designed to reduce IRF3 gene expression impaired the ability of the transfected empty vector to induce IFN- and to up-regulate MHC class I and costimulatory molecules in muscle cells and impaired the ability of transfected pOVA muscle cells to stimulate OT-1 cells. The experiments demonstrate that muscle cells transfected with a DNA vaccine can function as APCs to process and present the encoded Ag and activate Ag-specific CD8+ T cells. Neuropeptide ICE(R)S Inflammation
Calcitonin gene-related peptide (CGRP) is released from sensory nerves and mediates interactions between the nervous and immune systems. CGRP limits the in vivo injury from bacteria or LPS in mice, but the molecular mechanisms are not known. On p. 607
Harzenetter et al. generated mouse bone marrow-derived dendritic cells (BMDCs) and measured high levels of mRNAs for the CGRP receptor subunits. Treatment of the cells with CGRP increased intracellular cAMP levels and reduced TNF- release in response to stimulation with several TLR agonists; a CGRP peptide with a truncated N terminus had no effect. Experiments using actinomycin D showed that CGRP acted at the level of TNF- transcription. CGRP-induced inhibition occurred in TLR agonist-stimulated BMDCs from IL-10–/– mice. An adenylyl cyclase activator or a specific agonist of protein kinase A mimicked the CGRP inhibition of TNF- production on stimulated BMDCs but did not influence TLR signaling pathways. Inducible cAMP early repressor (ICER), the negative regulator of cAMP response element (CRE)-binding transcription factors, was expressed in stimulated BMDCs treated with CGRP but not in control cells. Cycloheximide inhibition of transcription prevented CGRP reduction of TNF- mRNA synthesis in stimulated cells. Reduced TNF- promoter activity was noted in LPS-treated macrophages cotransfected with plasmids expressing ICER plus a reporter gene under control of the TNF- promoter with the CRE-binding site. Mice injected with LPS plus CGRP had lower serum levels of TNF- and higher ICER mRNA levels in their livers compared with controls receiving LPS alone. The data are consistent with a model in which TNF- is suppressed by CGRP up-regulation of ICER via adenylyl cyclase and protein kinase A.
How Aspirin Reduces Inflammation
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Summaries written by Dorothy L. Buchhagen, Ph.D.
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