Bruton’s Tyrosine Kinase Is Required for TLR-Induced IL-10 Production

Schmidt, Nathan W.; Thieu, Vivian T.; Mann, Brandon A.; Ahyi, Ayele Nati N.; Kaplan, Mark H.

doi:10.4049/jimmunol.177.10.7203

Cited by 78 publications

(83 citation statements)

References 45 publications

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“…These observations correspond with earlier reports indicating that Btk plays a key role in macrophage stimulation by various TLRs (25). As an example, Btk has previously been demonstrated to be involved in TLR-dependent induction of pro-and anti-inflammatory cytokines (27,29). Moreover, Btk has been shown to mediate TLR8-and TLR9-dependent signaling in the human macrophage cell line THP-1 (47).…”

Section: Btk-mediated Ho-1 Induction By Lps Is Regulated Via the Transupporting

confidence: 78%

“…Because the Tec family kinase Btk has previously been shown to modulate gene expression in LPS-stimulated myeloid/macrophage cells (26,29) (for a review, see Ref. 25), we determined the effect of the specific pharmacological Btk inhibitor LFM-A13 on LPS-dependent HO-1 induction in the mouse macrophage cell line RAW264.7.…”

Section: Lps-dependent Ho-1 Gene Induction Is Blocked By the Specificmentioning

confidence: 99%

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Bruton’s Tyrosine Kinase Is Required for TLR-Dependent Heme Oxygenase-1 Gene Activation via Nrf2 in Macrophages

Vijayan

Baumgart-Vogt

Naidu

et al. 2011

The Journal of Immunology

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Heme oxygenase (HO)-1 is the inducible isoform of the rate-limiting enzyme of heme degradation and provides cytoprotection against oxidative stress by its products carbon monoxide and biliverdin. More recently, HO-1 has also been shown to exert immunomodulatory functions via cell type-specific anti-inflammatory effects in myeloid/macrophage cells. In the current study, it is demonstrated that Bruton's tyrosine kinase (Btk), the gene of which is mutated in the human immunodeficiency X-linked agammaglobulinemia, is involved in the upregulation of HO-1 gene expression via TLR signaling in macrophages. The specific Btk inhibitor LFM-A13 blocked HO-1 induction by the classical TLR4 ligand LPS in cell cultures of RAW264.7 monocytic cells and primary mouse alveolar macrophages. Moreover, upregulation of HO-1 gene expression was abrogated in LPS-stimulated alveolar macrophages from Btk−/− mice. Transfection studies with luciferase reporter gene constructs demonstrated that LPS-dependent induction of HO-1 promoter activity was attenuated by pharmacological Btk inhibition and by an overexpressed dominant-negative mutant of Btk. This induction was mediated by the transcription factor Nrf2, which is a master regulator of the antioxidant cellular defense. Accordingly, nuclear translocation of Nrf2 in LPS-treated macrophages was reduced by Btk inhibition. The generation of reactive oxygen species, but not that of NO, was involved in this regulatory pathway. Btk-dependent induction of HO-1 gene expression was also observed upon macrophage stimulation with ligands of TLR2, TLR6, TLR7, and TLR9, suggesting that Btk is required for HO-1 gene activation by major TLR pathways.

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Section: Btk-mediated Ho-1 Induction By Lps Is Regulated Via the Transupporting

confidence: 78%

Section: Lps-dependent Ho-1 Gene Induction Is Blocked By the Specificmentioning

confidence: 99%

Bruton’s Tyrosine Kinase Is Required for TLR-Dependent Heme Oxygenase-1 Gene Activation via Nrf2 in Macrophages

Vijayan

Baumgart-Vogt

Naidu

et al. 2011

The Journal of Immunology

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“…To understand further the mechanism by which the activation of TLR signaling in macrophages promoted tumor cell phagocytosis, we treated macrophages by combining TLR agonists with various inhibitors targeting key molecules that positively (MAPK, Btk) (23)(24)(25)(26)(27) or negatively (PI3K, caspase-1) (28,29) regulate TLR signaling. Blockers of MAPK, PI3K, and caspase-1 showed no effect on phagocytosis of cancer cells.…”

Section: Resultsmentioning

confidence: 99%

Macrophages eat cancer cells using their own calreticulin as a guide: Roles of TLR and Btk

Feng

Chen

Weissman-Tsukamoto

et al. 2015

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

222

199

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Macrophage-mediated programmed cell removal (PrCR) is an important mechanism of eliminating diseased and damaged cells before programmed cell death. The induction of PrCR by eat-me signals on tumor cells is countered by don’t-eat-me signals such as CD47, which binds macrophage signal-regulatory protein α to inhibit phagocytosis. Blockade of CD47 on tumor cells leads to phagocytosis by macrophages. Here we demonstrate that the activation of Toll-like receptor (TLR) signaling pathways in macrophages synergizes with blocking CD47 on tumor cells to enhance PrCR. Bruton’s tyrosine kinase (Btk) mediates TLR signaling in macrophages. Calreticulin, previously shown to be an eat-me signal on cancer cells, is activated in macrophages for secretion and cell-surface exposure by TLR and Btk to target cancer cells for phagocytosis, even if the cancer cells themselves do not express calreticulin.

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“…Activation of Btk was also found to be required for the TLR2-induced expression of TNF-␣ and IL-1␤ in primary human monocytes/macrophages (21,22). Btk is implicated in TLR-induced IL-10 production (23). But the findings of Horwood et al (22) revealed an unexpected level of complexity insofar as they showed that in primary human macrophages Btk is not required for TLR2-and TLR4-induced IL-6 and IL-8 release from X-linked agammaglobulinemia PBMC stimulated with LPS.…”

Section: Figurementioning

confidence: 99%

Etk/BMX, a Btk Family Tyrosine Kinase, and Mal Contribute to the Cross-Talk between MyD88 and FAK Pathways

Semaan¹,

Alsaleh²,

Gottenberg

et al. 2008

The Journal of Immunology

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MyD88 and focal adhesion kinase (FAK) are key adaptors involved in signaling downstream of TLR2, TLR4, and integrin α5β1, linking pathogen-associated molecule detection to the initiation of proinflammatory response. The MyD88 and integrin pathways are interlinked, but the mechanism of this cross-talk is not yet understood. In this study we addressed the involvement of Etk, which belongs to the Tec family of tyrosine kinases, in the cross-talk between the integrin/FAK and the MyD88 pathways in fibroblast-like synoviocyte s (FLS) and in IL-6 synthesis. Using small interfering RNA blockade, we report that Etk plays a major role in LPS- and protein I/II (a model activator of FAK)-dependent IL-6 release by activated FLS. Etk is associated with MyD88, FAK, and Mal as shown by coimmunoprecipitation. Interestingly, knockdown of Mal appreciably inhibited IL-6 synthesis in response to LPS and protein I/II. Our results also indicate that LPS and protein I/II induced phosphorylation of Etk and Mal in rheumatoid arthritis FLS via a FAK-dependent pathway. In conclusion, our data provide support that, in FLS, Etk and Mal are implicated in the cross-talk between FAK and MyD88 and that their being brought into play is clearly dependent on FAK.

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Bruton’s Tyrosine Kinase Is Required for TLR-Induced IL-10 Production

Cited by 78 publications

References 45 publications

Bruton’s Tyrosine Kinase Is Required for TLR-Dependent Heme Oxygenase-1 Gene Activation via Nrf2 in Macrophages

Bruton’s Tyrosine Kinase Is Required for TLR-Dependent Heme Oxygenase-1 Gene Activation via Nrf2 in Macrophages

Macrophages eat cancer cells using their own calreticulin as a guide: Roles of TLR and Btk

Etk/BMX, a Btk Family Tyrosine Kinase, and Mal Contribute to the Cross-Talk between MyD88 and FAK Pathways

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