A5085214045- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- NF-κB Signaling Pathways
- Cell death mechanisms and regulation
- Diabetes and associated disorders
- Ubiquitin and proteasome pathways
- Immune Response and Inflammation
- interferon and immune responses
- Immunotherapy and Immune Responses
- IL-33, ST2, and ILC Pathways
- Hepatitis B Virus Studies
- Immunodeficiency and Autoimmune Disorders
- Epigenetics and DNA Methylation
- Mitochondrial Function and Pathology
- Cancer-related Molecular Pathways
- T-cell and Retrovirus Studies
- Cancer Immunotherapy and Biomarkers
- Renal and related cancers
- ATP Synthase and ATPases Research
- Autophagy in Disease and Therapy
- Drug-Induced Hepatotoxicity and Protection
- Tuberculosis Research and Epidemiology
- Peptidase Inhibition and Analysis
- Eosinophilic Esophagitis
- Toxoplasma gondii Research Studies
National Institutes of Health
2010-2024
National Cancer Institute
2007-2024
Center for Cancer Research
2017-2024
National Institute of Diabetes and Digestive and Kidney Diseases
2013-2018
National Institute of Allergy and Infectious Diseases
2010-2015
University of Pittsburgh
1999-2007
Bid, a pro-apoptosis "BH3-only" member of the Bcl-2 family, can be cleaved by caspase-8 after Fas/TNF-R1 engagement. The p15 form truncated Bid (tBid) translocates to mitochondria and induces cytochrome <i>c</i> release, leading activation downstream caspases apoptosis. In current study, we investigated mechanism which tBid regulated cytochrome<i>c</i> release in terms its relationship mitochondrial permeability transition Bax, another family protein. We employed an <i>in vitro</i>...
Release of cytochrome c from the mitochondrial intermembrane space is critical to apoptosis induced by a variety death stimuli. Bid BH3-only prodeath Bcl-2 family protein that can potently activate this efflux. In current study, we investigated localization and its interactions with phospholipids, focusing on their relationships Bid-induced release. We found binding mitochondria required only three eight helical structures (alpha4-alpha6), but not BH3 domain, could be inhibited antideath...
The mitochondrial pathway is critical for the efficient execution of death receptor-initiated apoptosis in certain cell types. Questions remain as to why mitochondria are required that scenario. We investigated molecular events determined need by using an <i>in vivo</i> model anti-Fas-induced hepatocyte apoptosis. In wild-type mice, Fas stimulation resulted normal activation caspase-3, with generation active p19-p12 complex. In<i>bid</i>-deficient caspase-3 was arrested after initial...
Mutations in the TNF family of proteins have been associated with inherited forms immune deficiency. Using an array-based sequencing assay, we identified autosomal-dominant deficiency TNF-like weak inducer apoptosis (TWEAK; TNFSF12) a kindred recurrent infection and impaired antibody responses to protein polysaccharide vaccines. This mutation occurs sixth exon TWEAK results amino acid substitution R145C within conserved TNF-homology domain full-length protein. mutant formed high molecular...
Patients with hypomorphic mutations in STAT3 and patients hypermorphic STAT1 share several clinical cellular phenotypes suggesting overlapping pathophysiologic mechanisms. We, therefore, examined cytokine signaling CD4+ T cell differentiation these cohorts to characterize common pathways. As expected, of Th17 cells was impaired both cohorts. We found that hyperphosphorylated response stimulation STAT1-dependent PD-L1 up-regulation—known inhibit mouse models—was markedly enhanced as well....
Abstract Interactions between thymic epithelial cells (TEC) and developing thymocytes are essential for T cell development, but molecular insights on TEC thymus homeostasis still lacking. Here we identify distinct transcriptional programs of that account their age-specific properties, including proliferation rates, engraftability function. Further analyses Myc as a regulator fetal development to support the rapid increase size during life. Enforced expression in induces prolonged maintenance...
Tumor necrosis factor-alpha (TNFalpha)-induced cytotoxicity contributes to the pathogenesis in inflammatory and immune responses. Here, we studied role of pro-death Bcl-2 family proteins mitochondria apoptosis pathway development TNFalpha-induced hepatic injury during endotoxemia. After treating mice with lipopolysaccharide or TNFalpha presence d-galactosamine, Bid was cleaved translocated hepatocytes. Independently, Bax also activated by death receptor engagement mitochondria. However, its...
NIR (novel INHAT repressor) is a transcriptional co-repressor with inhibitor of histone acetyltransferase (INHAT) activity and has previously been shown to physically interact suppress p53 function. However, the mechanism by which suppresses not completely understood. Using proteomic approach, we have identified Aurora kinase B as novel binding partner NIR. We show that B, exist in protein complex binds NIR, thus also indirectly associates p53. Functionally, overexpression or activity,...
TRAF2 and ASK1 play essential roles in tumor necrosis factor α (TNF-α)-induced mitogen-activated protein kinase signaling. Stimulation through TNF receptor 2 (TNFR2) leads to ubiquitination subsequent proteasomal degradation. Here we show that TNFR2 signaling also selective degradation proteasomes. c-IAP1 was identified as the ubiquitin ligase for ubiquitination, studies with primary B cells from knock-out animals revealed is required TNFR2-induced Moreover, absence of TNFR2-mediated p38 JNK...
CYLD is a lysine 63-deubiquitinating enzyme that inhibits NF-κB and JNK signaling. Here, we show knock-out mice have markedly increased numbers of regulatory T cells (Tregs) in peripheral lymphoid organs but not the thymus. In vitro stimulation CYLD-deficient naive with anti-CD3/28 presence TGF-β led to marked increase number Foxp3-expressing when compared stimulated control CD4+ cells. Under endogenous conditions, formed complex Smad7 facilitated deubiquitination at 360 374 residues....
During autoimmunity, the normal ability of dendritic cells (DCs) to induce T-cell tolerance is disrupted; therefore, autoimmune disease therapies based on cell types and molecular pathways that elicit in steady state may not be effective. To determine which DC subsets context chronic we used chimeric antibodies specific for inhibitory receptor 2 (DCIR2) or DEC-205 target self-antigen CD11b(+) (cDC2) DCs CD8(+) (cDC1) DCs, respectively, autoimmune-prone nonobese diabetic (NOD) mice. Antigen...
Chromosomal translocations between loci encoding MALT1 and c-IAP2 are common in MALT lymphomas. The resulting fusion proteins lack the RING domain, region responsible for its ubiquitin protein ligase (E3) activity. Ectopic expression of activates canonical NF-κB signaling cascade, but how it does so is controversial promotes lymphoma unknown. Considering recent reports implicating c-IAP1 E3 activity repression non-canonical signaling, we asked if c-IAP2/MALT can initiate activation. Here...
1 Abstract The transcription factor TCF-1 (encoded by Tcf7) plays critical roles in several lineages of hematopoietic cells. In this study, we examined the molecular basis for Tcf7 regulation T cells, innate lymphoid and migratory conventional dendritic cells that find express Tcf7. We identified a 1kb regulatory element crucial initiation expression but dispensable Tcf7-expressing Within region, Notch binding site important not Our work establishes same is used distinct transcriptional...
NADPH oxidase-2 (Nox2)/gp91phox and p47phox deficient mice are prone to hyper-inflammatory responses suggesting a paradoxical role for Nox2-derived reactive oxygen species (ROS) as anti-inflammatory mediators. The molecular basis this mode of control remains unclear. Here we demonstrate that IFNγ/LPS matured p47phox−/−-ROS mouse dendritic cells (DC) secrete more IL-12p70 than similarly treated wild type DC, in an vitro co-culture model p47phox−/− DC bias ovalbumin-specific CD4+ T lymphocytes...
IL-12 and IL-23 are produced by activated antigen-presenting cells but the two induce distinct immune responses promoting Th1 Th17 cell differentiation, respectively. is a heterodimeric cytokine consisting of subunits: p40 that shared with p19 unique to IL-23. In this study, we showed production not was negatively regulated protein phosphatase 2A (PP2A) in dendritic (DC). PP2A inhibits suppressing expression IL-23p19 gene. Treating DC okadaic acid activity or knocking down catalytic subunit...
ABSTRACT DCs are important mediators of peripheral tolerance for the prevention autoimmunity. Chimeric αDEC-205 antibodies with attached antigens allow in vivo antigen-specific stimulation T cells by CD8+ DCs, resulting nonautoimmune mice. However, it is not clear whether DC-mediated induction occurs context ongoing We assessed role autoreactive CD4+ NOD mouse model type 1 diabetes. Targeting antigen to via led proliferation and expansion β-cell specific BDC2.5 cells. These also produced...
The thymus is critical for the establishment of adaptive immune system and development a diverse T cell repertoire. depends upon cell-cell interactions with epithelial cells in thymus. composed two different types cells: cortical medullary cells. Both these express critically depend on transcription factor Foxn1Foxn1 also expressed hair follicle, disruption Foxn1 function mice results severe thymic developmental defects hairless (nude) phenotype. Despite its importance, little known about...