A5011251458- NF-κB Signaling Pathways
- Immune Cell Function and Interaction
- interferon and immune responses
- Immune Response and Inflammation
- Cytokine Signaling Pathways and Interactions
- Immunotherapy and Immune Responses
- CAR-T cell therapy research
- Neuroinflammation and Neurodegeneration Mechanisms
- Cancer Immunotherapy and Biomarkers
- Protein Degradation and Inhibitors
- RNA Research and Splicing
- Inflammatory mediators and NSAID effects
- Multiple Myeloma Research and Treatments
- Systemic Lupus Erythematosus Research
- Mechanisms of cancer metastasis
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Inflammasome and immune disorders
- Cancer Mechanisms and Therapy
AstraZeneca (United Kingdom)
2018-2022
MRC Protein Phosphorylation and Ubiquitylation Unit
2014-2016
University of Dundee
2015-2016
Medical Research Council
2014-2016
Consejo Superior de Investigaciones Científicas
2010-2012
Universidad Autónoma de Madrid
2008-2011
Instituto de Investigaciones Biomédicas Sols-Morreale
2008-2011
Significance NF-κB and IFN Regulatory Factor 5 (IRF5) are required for the transcription of many proinflammatory cytokines in myeloid cells. The protein kinase IKKβ is major activator but how IRF5 activated has been unclear. This paper demonstrates that also activates by catalyzing phosphorylation Ser462. this serine induces dimerization its translocation to nucleus. activation master factors innate immune system same provides a mechanism coordinated control response inflammatory stimuli.
LPS stimulation activates IKK and different MAP kinase pathways, as well the PI3K-Akt-mTOR-p70 S6k pathway, a negative regulator of these MyD88-dependent intracellular signals. Here, we show that Cot/tpl2, MAP3K responsible for activation MKK1-Erk1/2, controls P-Ser473 Akt P-Thr389 p70 phosphorylation in LPS-stimulated macrophages. Analysis signalling Cot/tpl2 KO macrophages versus WT reveals lower IκBα recovery higher JNK p38α after 1 h stimulation. Moreover, deficiency increases...
Abstract Polymorphisms in the TNIP1 gene encoding A20-binding inhibitor of NF-κB1 (ABIN1) predispose to lupus and other autoimmune diseases at least eight human populations. We found previously that knock-in mice expressing a ubiquitin-binding–defective mutant ABIN1 (ABIN1[D485N]) develop autoimmunity as they age succumb disease resembling nephritis humans. In this article, we report Flt3-derived dendritic cells from these overproduced type 1 IFNs upon stimulation with ligands activate TLR7...
The concept of exploiting tumor intrinsic deficiencies in DNA damage repair mechanisms by inhibiting compensatory pathways is well established. For example, ATM-deficient cells show increased sensitivity to the ATR inhibitor ceralasertib. response (DDR)-deficient are also more sensitive damaging agents like crosslinker pyrrolobenzodiazepine (PBD) SG-3199. However, additional antitumor benefits from targeting DDR pathways, which could operate through activation innate immune system less...
Cot/tpl2 is the only MAP3K that activates MKK1/2-Erk1/2 in Toll-like receptor-activated macrophages. Here we show regulates RSK, S6 ribosomal protein, and 4E-BP phosphorylation after stimulation of bone marrow-derived macrophages with lipopolysaccharide (LPS), poly I:C, or zymosan. The dissociation 4E-BP-eIF4E complex, a key event cap-dependent mRNA translation initiation, dramatically reduced LPS-stimulated Cot/tpl2-knockout (KO) versus wild-type (Wt) Accordingly, LPS activation, increased...
Cot/tpl2 (also known as MAP3K8) has emerged a new and potentially interesting therapeutic anti-inflammatory target. Here, we report the first study of involvement in acute peripheral inflammation vivo. Six hours after an intraplantar injection zymosan, Cot/tpl2(-/-) mice showed 47% reduction myeloperoxidase activity, concomitant with 46% lower neutrophil recruitment 40% decreased luminol-mediated bioluminescence imaging Accordingly, deficiency provoked 25-30% together 65% macrophage 4 h...
In vitro assays that evaluate CD8+ T cell-mediated cytotoxicity are important to aid in the development of novel therapeutic approaches enhance anti-tumor immune responses. Here, we describe a co-culture assay circumvents problem highly variable allogeneic responses and obviates constraints HLA-restriction between effector target cells. We show this can be easily applied panel tumor cell lines provide additional insights into intrinsic drivers sensitivity/resistance killing, impact targeted...
PLK (Polo-like kinase) inhibitors, such as BI-2536, have been reported to suppress IFNB (encoding IFNβ, interferon β) gene transcription induced by ligands that activate TLR3 (Toll-like receptor 3) and TLR4. In the present study, we found BI-2536 is likely exert this effect preventing interaction of factors IRF3 (interferon-regulatory factor c-Jun with promoter, but without affecting TBK1 {TANK [TRAF (tumour-necrosis-factor-receptor-associated factor)-associated nuclear κB activator]-binding...
Introduction Immunotherapy has had a significant impact on the landscape of cancer treatment. However, with only 20%–30% response rate, identifying novel tumour intrinsic mechanisms resistance is key to advancing treatment success. Activation CD8 + T cells, main cellular mediators adaptive immunity, requires both cell receptor (TCR) binding MHC bound peptides and co-stimulation by antigen presenting cells (APCs). On recognition, antigen-specific become reactivated, leading lysis. Therefore,...