Tyrosine Kinase Btk Is Required for NK Cell Activation

Bao, Yan; Zheng, Jian; Han, Chaofeng; Jin, Jing; Han, Ho Jae; Liu, Yinping; Lau, Yu Lung; Tu, Wenwei; Cao, Xuetao

doi:10.1074/jbc.m112.372425

Cited by 66 publications

(55 citation statements)

References 36 publications

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“…34,38 A direct role of Btk in NK cell activation and cytotoxicity has emerged from work with Btk knock-out mice as well as in patients with X-linked agammaglobulinemia. 39 In the latter study, however, TLR3 rather than FcγR-mediated signaling was investigated. Interestingly ibrutinib has also been shown recently to inhibit Itk, another Tec family kinase like Btk.…”

Section: Discussionmentioning

confidence: 99%

Ibrutinib interferes with the cell-mediated anti-tumor activities of therapeutic CD20 antibodies: implications for combination therapy

et al. 2014

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Section: Discussionmentioning

confidence: 99%

Ibrutinib interferes with the cell-mediated anti-tumor activities of therapeutic CD20 antibodies: implications for combination therapy

et al. 2014

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“…Furthermore, Mal displays a great inhibitory role for TLR3 signaling to c-Jun N-terminal kinase (JNK) and IL-6 induction [35], but its role in mediating HO-1 expression is still unknown. Btk and c-Src, two non-receptor tyrosine protein kinases, have been shown to play multiple roles in macrophage-mediated innate immunity [36], [37]. Activated Btk and c-Src could phosphorylate their downstream of kinases, such as phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt [38].…”

Section: Introductionmentioning

confidence: 99%

Macrophage-Activating Lipopeptide-2 Requires Mal and PI3K for Efficient Induction of Heme Oxygenase-1

et al. 2014

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AimsThis study is to investigate the mechanisms by which macrophage-activating lipopeptide-2 (MALP-2) induces heme oxygenase (HO)-1, a cytoprotective enzyme that catalyzes the degradation of heme, in human monocytes.MethodsHuman monocytic THP-1 cells were cultured for transient transfection with plasmids and stimulation with MALP-2 for indicative time intervals. After incubation with MALP-2, cells were collected and disrupted, before being tested for promoter activity using luciferase assay. For analysis of proteins, immunoreactive bands were detected using an enhanced chemiluminescence Western blotting system, and the band intensity was measured by densitometryic analysis. For the detection of co-immunoprecipitation, SDS-PAGE was performed and the membranes were probed using respective antibodies. To investigate the cellular localization of NF-E2-related factor 2 (Nrf2), cells underwent immunofluorescence staining and confocal microscopy, and were analyzed using electrophoretic mobility shift assay.ResultsMALP-2-induced HO-1 expression and promoter activity were abrogated by transfection with dominant negative (DN) plasmids of TLR2 and TLR6, or their neutralizing antibodies. However, inhibition of MyD88 or transfection with the DN-MyD88 was insufficient to attenuate HO-1 expression. In contrast, mutation or silencing of MyD88 adapter-like (Mal) by DN-Mal or siRNA almost completely blocked HO-1 induction. Btk, c-Src and PI3K were also involved in MALP-2-induced HO-1 expression, as revealed by specific inhibitors LFM-A13, PP1 and LY294002, or by transfection with siRNA of c-Src. MALP-2-induced activation of PI3K was attenuated by transfection with DN mutant of Mal, and by pretreatment with LFM-A13 or PP1. Furthermore, MALP-2 stimulated the translocation of Nrf2 from the cytosol to the nucleus and Nrf2 binding to the ARE site in the HO-1 promoter, which could also be inhibited by pretreatment with a PI3K inhibitor, LY294002.ConclusionsThese results indicated that MALP-2 required TLR2/6, Btk, Mal and c-Src to activate PI3K, which in turn initiated the activation of Nrf2 for efficient HO-1 induction.

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“…It has been reported that NK cells can also undergo apoptosis following activation via cytokine receptors (31). Ibrutinib targets such as ITK and BTK also play an important role in NK cell function and signaling processes (32,33). Therefore, we investigated if acalabrutinib (Supplemental Figure 1B).…”

Section: Ibrutinib Treatment Increases Numbers Of Both Cd4mentioning

confidence: 99%

Ibrutinib treatment improves T cell number and function in CLL patients

Long

Beckwith

et al. 2017

Journal of Clinical Investigation

313

343

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BACKGROUND.Ibrutinib has been shown to have immunomodulatory effects by inhibiting Bruton's tyrosine kinase (BTK) and IL-2-inducible T cell kinase (ITK). The relative importance of inhibiting these 2 kinases has not been examined despite its relevance to immune-based therapies. METHODS.Peripheral blood mononuclear cells from chronic lymphocytic leukemia (CLL) patients on clinical trials of ibrutinib (BTK/ITK inhibitor; n = 19) or acalabrutinib (selective BTK inhibitor; n = 13) were collected serially. T cell phenotype, immune function, and CLL cell immunosuppressive capacity were evaluated. RESULTS. Ibrutinib markedly increased CD4+ and CD8 + T cell numbers in CLL patients. This effect was more prominent in effector/effector memory subsets and was not observed with acalabrutinib. Ex vivo studies demonstrated that this may be due to diminished activation-induced cell death through ITK inhibition. PD-1 and CTLA-4 expression was significantly markedly reduced in T cells by both agents. While the number of Treg cells remained unchanged, the ratio of these to conventional CD4 + T cells was reduced with ibrutinib, but not acalabrutinib. Both agents reduced expression of the immunosuppressive molecules CD200 and BTLA as well as IL-10 production by CLL cells. CONCLUSIONS. Ibrutinib treatment increased the in vivo persistence of activated T cells, decreased the Treg/CD4+ T cell ratio, and diminished the immune-suppressive properties of CLL cells through BTK-dependent and -independent mechanisms. These features provide a strong rationale for combination immunotherapy approaches with ibrutinib in CLL and other cancers. TRIAL REGISTRATION. ClinicalTrials.gov NCT01589302 and NCT02029443. Samples described here were collected per OSU-0025.

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Tyrosine Kinase Btk Is Required for NK Cell Activation

Abstract: Background: Whether Btk is involved in the regulation of NK cell innate function remains unknown. Results: BtkϪ/Ϫ murine and human NK cells have decreased innate immune responses to the TLR3 ligand.

Cited by 66 publications

References 36 publications

Ibrutinib interferes with the cell-mediated anti-tumor activities of therapeutic CD20 antibodies: implications for combination therapy

Ibrutinib interferes with the cell-mediated anti-tumor activities of therapeutic CD20 antibodies: implications for combination therapy

Macrophage-Activating Lipopeptide-2 Requires Mal and PI3K for Efficient Induction of Heme Oxygenase-1

Ibrutinib treatment improves T cell number and function in CLL patients

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