ArticleBlood2012
p38 MAPK inhibition suppresses the TLR-hypersensitive phenotype in FANCC- and FANCA-deficient mononuclear phagocytes.
Article in Blood, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 35 citations in OpenAlex.
- High content drug screening for Fanconi anemia therapeutics.Orphanet journal of rare diseases · 2020Article
- Microphthalmia transcription factor expression contributes to bone marrow failure in Fanconi anemia.The Journal of clinical investigation · 2020Article
- Natural Killer Cell Degranulation Defect: A Cause for Impaired NK-Cell Cytotoxicity and Hyperinflammation in Fanconi Anemia Patients.Frontiers in immunology · 2019Article
- Cell-Cycle-Specific Function of p53 in Fanconi Anemia Hematopoietic Stem and Progenitor Cell Proliferation.Stem cell reports · 2018Article
- Recent advances in understanding hematopoiesis in Fanconi Anemia.F1000Research · 2018Review
- PlGF enhances TLR-dependent inflammatory responses in human mononuclear phagocytes.American journal of reproductive immunology (New York, N.Y. : 1989) · 2017Article
- Identification of Interleukin-1 by Functional Screening as a Key Mediator of Cellular Expansion and Disease Progression in Acute Myeloid Leukemia.Cell reports · 2017Article
- Endogenous DNA Damage Leads to p53-Independent Deficits in Replicative Fitness in Fetal Murine Fancd2Stem cell reports · 2016Article
- Increased red cell distribution width in Fanconi anemia: a novel marker of stress erythropoiesis.Orphanet journal of rare diseases · 2016Article
- Cytokine overproduction and crosslinker hypersensitivity are unlinked in Fanconi anemia macrophages.Journal of leukocyte biology · 2016Article
- Fanconi Anemia Mesenchymal Stromal Cells-Derived Glycerophospholipids Skew Hematopoietic Stem Cell Differentiation Through Toll-Like Receptor Signaling.Stem cells (Dayton, Ohio) · 2015Article
- Toll-like receptor signaling in hematopoietic homeostasis and the pathogenesis of hematologic diseases.Frontiers of medicine · 2015Review
- Modelling Fanconi anemia pathogenesis and therapeutics using integration-free patient-derived iPSCs.Nature communications · 2014Article
- Regulation of macrophage biology by lithium: a new look at an old drug.Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2014Review
- Article
- Cytokine production by bone marrow mononuclear cells in inherited bone marrow failure syndromes.British journal of haematology · 2013Article
- Gene expression profiles in engineered cardiac tissues respond to mechanical loading and inhibition of tyrosine kinases.Physiological reports · 2013Article
- Toll-like receptor alterations in myelodysplastic syndrome.Leukemia · 2013Article
- Elevated levels of STAT1 in Fanconi anemia group A lymphoblasts correlate with the cells' sensitivity to DNA interstrand crosslinking drugs.Haematologica · 2013Article
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
Abstract
Fanconi anemia, complementation group C (FANCC)-deficient hematopoietic stem and progenitor cells are hypersensitive to a variety of inhibitory cytokines, one of which, TNFα, can induce BM failure and clonal evolution in Fancc-deficient mice. FANCC-deficient macrophages are also hypersensitive to TLR activation and produce TNFα in an unrestrained fashion. Reasoning that suppression of inhibitory cytokine production might enhance hematopoiesis, we screened small molecules using TLR agonist-stimulated FANCC- and Fanconi anemia, complementation group A (FANCA)-deficient macrophages containing an NF-κB/AP-1-responsive reporter gene (SEAP). Of the 75 small molecules screened, the p38 MAPK inhibitor BIRB 796 and dasatinib potently suppressed TLR8-dependent expression of the reporter gene. Fanconi anemia (FA) macrophages were hypersensitive to the TLR7/8 activator R848, overproducing SEAP and TNFα in response to all doses of the agonist. Low doses (50nM) of both agents inhibited p38 MAPK-dependent activation of MAPKAPK2 (MK2) and suppressed MK2-dependent TNFα production without substantially influencing TNFα gene transcription. Overproduction of TNFα by primary FA cells was likewise suppressed by these agents and involved inhibition of MK2 activation. Because MK2 is also known to influence production and/or sensitivity to 2 other suppressive factors (MIP-1α and IFNγ) to which FA hematopoietic progenitor cells are uniquely vulnerable, targeting of p38 MAPK in FA hematopoietic cells is a rational objective for preclinical evaluation.
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Registered trials
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