Bruton's Tyrosine Kinase Is Required For Lipopolysaccharide-induced Tumor Necrosis Factor α Production

Horwood, Nicole J.; Mahon, Tara; McDaid, John; Campbell, Jamie I. D.; Mano, Hiroyuki; Brennan, Fionula M.; Webster, David; Foxwell, Brian M. J.

doi:10.1084/jem.20021845

Cited by 141 publications

(188 citation statements)

References 45 publications

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“…We show that dasatinib inhibits the secretion of histamine and IL-6 from mast cells and basophils, as well as TNF-␣ secretion from U937 cells, all of which depend on the kinase activity of Btk (28,31). Dasatinib is an inhibitor with a broad specificity, also termed multitarget inhibitor.…”

Section: Discussionmentioning

confidence: 99%

“…To assess the physiological consequences of Btk inhibition, we determined the impact of dasatinib on the secretion of TNF-␣ and IL-6, which were described to depended on Btk (28,31,32). Firstly, TNF-␣ release of vitamin D3-differentiated U937 cells was measured in the presence of different concentrations of dasatinib and imatinib.…”

Section: Mutation Of the Gatekeeper Residue In Itk Confers Sensitivitmentioning

confidence: 99%

“…To assess the activity of dasatinib in cultured cells, vitamin D3-differentiated U937 cells were chosen, which activate Btk in response to LPS stimulation (28). Dasatinib (30 nM) led to a clear reduction of Btk autophosphorylation on Tyr-223, which is used as a marker for in vivo Btk kinase activity (29).…”

Section: Dasatinib Inhibits Btk and Tec Kinase Activity In Vitro Andmentioning

confidence: 99%

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The Btk tyrosine kinase is a major target of the Bcr-Abl inhibitor dasatinib

Hantschel

Rix

Schmidt

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

263

224

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Section: Discussionmentioning

confidence: 99%

Section: Mutation Of the Gatekeeper Residue In Itk Confers Sensitivitmentioning

confidence: 99%

Section: Dasatinib Inhibits Btk and Tec Kinase Activity In Vitro Andmentioning

confidence: 99%

See 1 more Smart Citation

The Btk tyrosine kinase is a major target of the Bcr-Abl inhibitor dasatinib

Hantschel

Rix

Schmidt

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

263

224

View full text Add to dashboard Cite

“…Bruton's tyrosine kinase is a critical tyrosine kinase in TLR4, TLR7 and TLR9 signaling for activating NF-kB. 81 miR-346 is strongly induced by LPS treatment and targets Btk mRNA in the synovial fibroblasts of rheumatoid arthritis patients. 82 Whether miR-346 targets Btk in macrophages needs to be further studied.…”

Section: Mirnas In Regulation Of Tlr and Rig-i Pathways Yk LI And Xymentioning

confidence: 99%

MicroRNAs in the regulation of TLR and RIG-I pathways

2012

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The innate immune system recognizes invading pathogens through germline-encoded pattern recognition receptors (PRRs), which elicit innate antimicrobial and inflammatory responses and initiate adaptive immunity to control or eliminate infection. Toll-like receptors (TLRs) and retinoic acid-inducible gene I (RIG-I) are the key innate immune PRRs and are tightly regulated by elaborate mechanisms to ensure a beneficial outcome in response to foreign invaders. Although much of the focus in the literature has been on the study of protein regulators of inflammation, microRNAs (miRNAs) have emerged as important controllers of certain features of the inflammatory process. Several miRNAs are induced by TLR and RIG-I activation in myeloid cells and act as feedback regulators of TLR and RIG-I signaling. In this review, we comprehensively discuss the recent understanding of how miRNA networks respond to TLR and RIG-I signaling and their role in the initiation and termination of inflammatory responses. Increasing evidence also indicates that both virus-encoded miRNAs and cellular miRNAs have important functions in viral replication and host anti-viral immunity.

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“…We have shown that Btk is recruited to the LPS receptor Toll-like receptor-4 (TLR4) where it is activated and is required for NFB activation (6). In addition, peripheral blood mononuclear cells (PBMCs) isolated from XLA patients have been shown to have impaired TNF␣ production induced by LPS (7).…”

mentioning

confidence: 99%

Bruton's Tyrosine Kinase Is Involved in p65-mediated Transactivation and Phosphorylation of p65 on Serine 536 during NFκB Activation by Lipopolysaccharide

Doyle

Jefferies²,

O’Neill³

2005

Journal of Biological Chemistry

131

102

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Bruton's tyrosine kinase (Btk) has recently been shown to participate in the induction of nuclear factor B (NFB)-dependent gene expression by the lipopolysaccharide (LPS) receptor Toll-like receptor-4 (TLR4). In this study we have examined the mechanism whereby Btk participates in this response. Treatment of the murine monocytic cell line Raw264.7 with LFM-A13, a specific Btk inhibitor, blocked LPS-induced NFB-dependent reporter gene expression but not IB␣ degradation. Transient transfection of HEK293 cells with Btk had no effect on NFB-dependent reporter gene expression but strongly promoted transactivation of a reporter gene by a p65-Gal4 fusion protein. IB␣ degradation activated by LPS was intact in macrophages from X-linked immunodeficiency (Xid) mice, which contain inactive Btk. Transfection of cells with a dominant negative form of Btk (BtkK430R) inhibited LPS-driven p65 mediated transactivation. Additionally LFM-A13 impaired phosphorylation of serine 536 on p65 induced by LPS in HEK293-TLR4 cells, and in Xid macrophages this response was impaired. This study therefore reveals a novel function for Btk. It is required for the signaling pathway activated by TLR4, which culminates in phosphorylation of p65 on serine 536 promoting transactivation by NFB.Bruton's tyrosine kinase (Btk) 1 is a member of the Tec family of non-receptor tyrosine kinases and is found in all cells of the hematopoietic lineage except plasma cells and T-cells (1). In B-cells, activation of the B-cell receptor leads to Btk being rapidly recruited to the plasma membrane where it becomes phosphorylated and activated. Btk is required for normal B-cell development (2) and the gene encoding Btk was first identified as the mutated gene in X-linked agammaglobulinemia (XLA) in humans, an immune disease characterized by a lack of circulating B lymphocytes and an absence of Igs of all classes (3). Mutations in the Btk gene also result in the less severe Xlinked immunodeficiency (Xid) in mice. Various mutations have been identified as being responsible for the XLA phenotype, whereas the mutation in Xid mice has been mapped to arginine 28 (R28C) in the PH domain (4). This prevents Btk associating with the membrane, thus inactivating it. The PH domain is important in the process of Btk activation, since it localizes Btk to the membrane through its interaction with phosphatidylinositol triphosphate (PIP 3 ), which is generated by phosphatidylinositol 3-kinase (PI3K).Due to the major phenotype of Btk deficiency being impaired B-cell development and function, the main focus of interest in Btk has centered around the B-cell. However, several studies have provided a more general role for Btk in immune regulation. Studies in Xid peritoneal macrophages have shown reduced responses to lipopolysaccharide (LPS) stimulation, with tumor necrosis factor ␣ (TNF␣) and IL-1␤ production decreased and macrophage effector functions impaired (5). We have shown that Btk is recruited to the LPS receptor Toll-like receptor-4 (TLR4) where it is activated and is required f...

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Bruton's Tyrosine Kinase Is Required For Lipopolysaccharide-induced Tumor Necrosis Factor α Production

Cited by 141 publications

References 45 publications

The Btk tyrosine kinase is a major target of the Bcr-Abl inhibitor dasatinib

The Btk tyrosine kinase is a major target of the Bcr-Abl inhibitor dasatinib

MicroRNAs in the regulation of TLR and RIG-I pathways

Bruton's Tyrosine Kinase Is Involved in p65-mediated Transactivation and Phosphorylation of p65 on Serine 536 during NFκB Activation by Lipopolysaccharide

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