Dataset Information

Overexpression of the toll-like receptor (TLR) signaling adaptor MYD88, but lack of genetic mutation, in myelodysplastic syndromes.

ABSTRACT: MYD88 is a key mediator of Toll-like receptor innate immunity signaling. Oncogenically active MYD88 mutations have recently been reported in lymphoid malignancies, but has not been described in MDS. To characterize MYD88 in MDS, we sequenced the coding region of the MYD88 gene in 40 MDS patients. No MYD88 mutation was detected. We next characterized MYD88 expression in bone marrow CD34+ cells (N?=?64). Increased MYD88 RNA was detected in 40% of patients. Patients with higher MYD88 expression in CD34+ cells had a tendency for shorter survival compared to the ones with lower MYD88, which was significant when controlled for IPSS and age. We then evaluated effect of MYD88 blockade in the CD34+ cells of patients with lower-risk MDS. Colony formation assays indicated that MYD88 blockade using a MYD88 inhibitor resulted in increased erythroid colony formation. MYD88 blockade also negatively regulated the secretion of interleukin-8. Treatment of MDS CD34+ cells with an IL-8 antibody also increased formation of erythroid colonies. These results indicate that MYD88 plays a role in the pathobiology of MDS and may have prognostic and therapeutic value in the management of patients with this disease.

SUBMITTER: Dimicoli S

PROVIDER: S-EPMC3744562 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

Overexpression of the toll-like receptor (TLR) signaling adaptor MYD88, but lack of genetic mutation, in myelodysplastic syndromes.

Dimicoli Sophie S Wei Yue Y Bueso-Ramos Carlos C Yang Hui H Dinardo Courtney C Jia Yu Y Zheng Hong H Fang Zhihong Z Nguyen Martin M Pierce Sherry S Chen Rui R Wang Hui H Wu Chenghua C Garcia-Manero Guillermo G

PloS one 20130815 8

MYD88 is a key mediator of Toll-like receptor innate immunity signaling. Oncogenically active MYD88 mutations have recently been reported in lymphoid malignancies, but has not been described in MDS. To characterize MYD88 in MDS, we sequenced the coding region of the MYD88 gene in 40 MDS patients. No MYD88 mutation was detected. We next characterized MYD88 expression in bone marrow CD34+ cells (N = 64). Increased MYD88 RNA was detected in 40% of patients. Patients with higher MYD88 expression in ...[more]

PMID: 23976989

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Project description:UnlabelledThe Toll-like receptor 4 (TLR4) that recognizes endotoxin, a trigger of inflammation in alcoholic liver disease (ALD), activates two signaling pathways utilizing different adapter molecules: the common TLR adapter, myeloid differentiation factor 88 (MyD88), or Toll/interleukin immune-response-domain-containing adaptor inducing interferon (IFN)-beta. The MyD88 pathway induces proinflammatory cytokine activation, a critical mediator of ALD. Here we evaluated the role of MyD88 in alcohol-induced liver injury in wild-type, TLR2-deficient, TLR4-deficient, or MyD88-deficient (knockout [KO]) mice after administration of the Lieber-De-Carli diet (4.5% volume/volume ethanol) or an isocaloric liquid control diet for 5 weeks. Alcohol feeding resulted in a significant increase in serum alanine aminotransferase levels, liver steatosis and triglyceride levels suggesting liver damage in WT, TLR2-KO, and MyD88-KO but not in TLR4-KO mice. Expression of inflammatory mediators (tumor necrosis factor-alpha and interleukin-6) and TLR4 coreceptors (CD14 and MD2) was significantly higher in livers of alcohol-fed WT, TLR2-KO, or MyD88-KO, but not in TLR4-KO mice, compared to controls. Reactive oxygen radicals produced by cytochrome P450 and the nicotinamide adenine dinucleotide phosphate complexes contribute to alcoholic liver damage. Alcohol feeding-induced expression and activation of cytochrome P450 and the nicotinamide adenine dinucleotide phosphate complex were prevented by TLR4-deficiency but not by MyD88-deficiency. Liver expression of interferon regulatory factor 3 (IRF3), a MyD88-independent signaling molecule, was not affected by chronic alcohol treatment in whole livers of WT mice or in any of the KO mice. However, the induction of IRF7, an IRF3-inducible gene, was found in Kupffer cells of alcohol-fed WT mice. Alcohol feeding also induced nuclear factor-kappaB activation in a TLR4-dependent MyD88-independent manner.ConclusionWhile TLR4 deficiency was protective, MyD88 deficiency failed to prevent alcohol-induced liver damage and inflammation. These results suggest that the common TLR adapter, MyD88, is dispensable in TLR4-mediated liver injury in ALD.

Dataset Information

Overexpression of the toll-like receptor (TLR) signaling adaptor MYD88, but lack of genetic mutation, in myelodysplastic syndromes.

Publications

Overexpression of the toll-like receptor (TLR) signaling adaptor MYD88, but lack of genetic mutation, in myelodysplastic syndromes.

Similar Datasets

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