Analysis of the Genetic Expression of Inflammatory Mediators From Patients with Spontaneous Deep Venous Thrombosis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5251-5251
Author(s):  
Aline Barnabé ◽  
Fernanda Dutra Santiago-Bassora ◽  
Andrey dos Santos ◽  
Marcelo Falsarella Carazzolle ◽  
Gonçalo AG Pereira ◽  
...  
Keyword(s):  
Gene Expression ◽  
Major Histocompatibility Complex ◽  
Venous Thrombosis ◽  
Deep Venous Thrombosis ◽  
Major Histocompatibility Complex Class ◽  
Inflammatory Mediators ◽  
Fold Increase ◽  
Class Ii ◽  
Complex Class ◽  
Histocompatibility Complex

Abstract Abstract 5251 Deep venous thrombosis (DVT) is a multifactorial disease and in about 30% of patients no risk factor can be identified. Association of inflammation and hemostasis is thought to play a significant role in the pathogenesis of DVT. We hypothesized that distinctive patterns of expression of inflammatory mediators in mononuclear cells from patients with previous DVT could be relevant to the pathogenesis of DVT. cDNA microarray technology (CodeLink Bioarrays) was chosen to study the gene expression profile of inflammatory mediators in DVT patients with clinical characteristics of a high penetrance of any putative hereditary risk, and their healthy siblings. These microarrays were hybridized with synthesized probes from pooled samples collected from patients and control siblings. Patients were divided into two clinical groups: (1) patients with one spontaneous DVT (n=2), and (2) patients with recurrent spontaneous DVT episodes (n=1). Preliminary analysis showed that 2% of approximately 55,000 transcripts contained in the array had significant (higher than 2-fold) differences in expression in spontaneous and recurrent spontaneous DVT relative to their asymptomatic siblings. In group 1, 738 genes were upregulated and 504 genes were downregulated. In group 2, 1229 genes were upregulated and 87 genes were downregulated. Genes with different expression compared to controls were associated to immune and inflammatory response, motility, cell adhesion, cell-cell signaling, defense response, signal transduction and apoptosis. Genes that presented the highest differences compared to controls were interleukin 8 (43-fold increase), chemokine (C-X-C motif) ligand 2 (11-fold increase), major histocompatibility complex, class II, DR beta 5 (8-fold increase), major histocompatibility complex, class II, DQ alpha 1 (29-fold decrease), caspase recruitment domain family, member 15 (7-fold increase), carboxypeptidase A5 (11-fold decrease), cathepsin G (8-fold decrease), and azurocidin 1 (3-fold decrease). A comprehensive list of these genes was generated. Evaluation of the significance of these distinctive gene expression profiles between patients with spontaneous and recurrent DVT compared to their asymptomatic siblings could reveal novel insights into the pathophysiology of the first DVT episode and of DVT recurrence, as well as new biomarkers or therapeutic targets. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The Major Histocompatibility Complex Class II Transactivator CIITA Inhibits the Persistent Activation of NF-κB by the Human T Cell Lymphotropic Virus Type 1 Tax-1 Oncoprotein

2016 ◽  
Vol 90 (7) ◽  
pp. 3708-3721 ◽  
Author(s):  
Greta Forlani ◽  
Rawan Abdallah ◽  
Roberto S. Accolla ◽  
Giovanna Tosi
Keyword(s):  
Gene Expression ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Major Histocompatibility Complex Class ◽  
Class Ii ◽  
Complex Class ◽  
Class Ii Transactivator ◽  
Histocompatibility Complex ◽  
Human T Cell

ABSTRACTHuman T cell lymphotropic virus type 1 (HTLV-1) Tax-1, a key protein in HTLV-1-induced T cell transformation, deregulates diverse cell signaling pathways. Among them, the NF-κB pathway is constitutively activated by Tax-1, which binds to NF-κB proteins and activates the IκB kinase (IKK). Upon phosphorylation-dependent IκB degradation, NF-κB migrates into the nucleus, mediating Tax-1-stimulated gene expression. We show that the transcriptional regulator of major histocompatibility complex class II genes CIITA (class II transactivator), endogenously or ectopically expressed in different cells, inhibits the activation of the canonical NF-κB pathway by Tax-1 and map the region that mediates this effect. CIITA affects the subcellular localization of Tax-1, which is mostly retained in the cytoplasm, and this correlates with impaired migration of RelA into the nucleus. Cytoplasmic and nuclear mutant forms of CIITA reveal that CIITA exploits different strategies to suppress Tax-1-mediated NF-κB activation in both subcellular compartments. CIITA interacts with Tax-1 without preventing Tax-1 binding to both IKKγ and RelA. Nevertheless, CIITA affects Tax-1-induced IKK activity, causing retention of the inactive p50/RelA/IκB complex in the cytoplasm. Nuclear CIITA associates with Tax-1/RelA in nuclear bodies, blocking Tax-1-dependent activation of NF-κB-responsive genes. Thus, CIITA inhibits cytoplasmic and nuclear steps of Tax-1-mediated NF-κB activation. These results, together with our previous finding that CIITA acts as a restriction factor inhibiting Tax-1-promoted HTLV-1 gene expression and replication, indicate that CIITA is a versatile molecule that might also counteract Tax-1 transforming activity. Unveiling the molecular basis of CIITA-mediated inhibition of Tax-1 functions may be important in defining new strategies to control HTLV-1 spreading and oncogenic potential.IMPORTANCEHTLV-1 is the causative agent of human adult T cell leukemia-lymphoma (ATLL). The viral transactivator Tax-1 plays a central role in the onset of ATLL, mostly by deregulating the NF-κB pathway. We demonstrate that CIITA, a key regulator of adaptive immunity, suppresses Tax-1-dependent activation of NF-κB by acting at several levels: it retains most of Tax-1 and RelA in the cytoplasm and inhibits their residual functional activity in the nucleus. Importantly, this inhibition occurs in cells that are targets of HTLV-1 infection. These findings are of interest in the field of virology because they expand the current knowledge of the functional relationship between viral products and cellular interactors and provide the basis for a better understanding of the molecular countermeasures adopted by the host cell to antagonize HTLV-1 spreading and transforming properties. Within this framework, our results may contribute to the establishment of novel strategies against HTLV-1 infection and virus-dependent oncogenic transformation.

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