Discovery and initial SAR of inhibitors of interleukin-1 receptor-associated kinase-4

Powers, Jay P.; Li, Shyun; Jaén, Juan C.; Liu, Jinqian; Walker, Nigel; Wang, Zhong Lin; Wesche, Holger

doi:10.1016/j.bmcl.2006.03.020

Cited by 108 publications

(84 citation statements)

References 9 publications

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“…6B). To further confirm the involvement of IRAK-4, we determined the Camp expression levels in BM-MSCs treated with an IRAK-4 inhibitor (300 M I5409; Sigma) (36). We observed a significant downregulation of Camp expression levels in IRAK-4 inhibitortreated cells compared to those in untreated cells (P Ͻ 0.001) (Fig.…”

Section: Upregulation Of Camp By Tlrs Is Mediated Via Myd88 and Il-1 mentioning

confidence: 96%

Mouse Bone Marrow Sca-1 ⁺ CD44 ⁺ Mesenchymal Stem Cells Kill Avirulent Mycobacteria but Not Mycobacterium tuberculosis through Modulation of Cathelicidin Expression via the p38 Mitogen-Activated Protein Kinase-Dependent Pathway

et al. 2017

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Mycobacterium tuberculosis primarily infects lung macrophages. However, a recent study showed that M. tuberculosis also infects and persists in a dormant form inside bone marrow mesenchymal stem cells (BM-MSCs) even after successful antibiotic therapy. However, the mechanism(s) by which M. tuberculosis survives in BM-MSCs is still not known. Like macrophages, BM-MSCs do not contain a well-defined endocytic pathway, which is known to play a central role in the clearance of internalized mycobacteria. Here, we studied the fate of virulent and avirulent mycobacteria in Sca-1 ϩ CD44 ϩ BM-MSCs. We found that BM-MSCs were able to kill avirulent Mycobacterium smegmatis and Mycobacterium bovis BCG but not the pathogenic species M. tuberculosis. Further mechanistic studies revealed that pathogenic M. tuberculosis dampens the antibacterial response of BM-MSCs by downregulating the expression of the cationic antimicrobial peptide cathelicidin. In contrast, avirulent mycobacteria were effectively killed by inducing the Toll-like receptor 2/4 (TLR2/4) pathway-dependent expression of cathelicidin, while small interfering RNA (siRNA)-mediated cathelicidin silencing increased the survival of M. bovis BCG in BMMSCs. We also showed that M. bovis BCG infection caused increased expression levels of MyD88, phospho-interleukin-1 receptor-associated kinase 4 (pIRAK-4), and the p38 mitogen-activated protein kinase (MAPK) signaling pathway. Further downstream investigations demonstrated that IRAK-4 -p38 activation increased the nuclear translocation of NF-B, which subsequently induced the expression of cathelicidin and the cytokine interleukin-1␤ (IL-1␤), resulting in the decreased survival of M. bovis BCG. On the other hand, inhibition of TLR2/4, pIRAK-4, p38, and NF-B nuclear translocation decreased cathelicidin and IL-1␤ expression levels and therefore increased the survival of avirulent mycobacteria. This is the first report that demonstrates that virulent mycobacteria manipulate the TLR2/4 -MyD88 -IRAK-4 -p38 -NF-B-Camp-IL-1␤ pathway to survive inside bone marrow stem cells.

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Section: Upregulation Of Camp By Tlrs Is Mediated Via Myd88 and Il-1 mentioning

confidence: 96%

Mouse Bone Marrow Sca-1 ⁺ CD44 ⁺ Mesenchymal Stem Cells Kill Avirulent Mycobacteria but Not Mycobacterium tuberculosis through Modulation of Cathelicidin Expression via the p38 Mitogen-Activated Protein Kinase-Dependent Pathway

et al. 2017

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“…BCWM.1, MWCL-1, and primary patient WM cells genotyped for MYD88 L265P, as well as MYD88 WT healthy donor CD19-selected PBMCs, and MYD88 WT cell lines were treated with and without inhibitors of MYD88 homodimerization (IMGENEX), IRAK 1 and 4 kinase function (EMDJ), 20,21 and/or BTK (ibrutinib; Pharmacyclics, Inc.). Cells were incubated at 37°C with either 100 mM of the MYD88 inhibitor or control peptides or 0.01 to 20 mM of the IRAK 1 and 4 or BTK kinase inhibitors.…”

Section: Inhibitors Of Myd88 Signalingmentioning

confidence: 99%

“…MYD88 is known to trigger IRAK1 phosphorylation leading to downstream IkBa phosphorylation, and promotion of NF-kB signaling which is important for WM cell growth and survival. 20,21 Moreover, inhibition of MYD88 signaling in L265P WM cell lines and primary WM patient cells leads to inhibition of NF-kB p65 phosphorylation and nuclear translocation. 3 We therefore examined the IRAK pathway to further clarify its impact on WM survival.…”

Section: Impact Of Myd88 Inhibition On Irak1 and Ikba Phosphorylationmentioning

confidence: 99%

A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenström macroglobulinemia

Yang

Zhou

Liu

et al. 2013

Blood

304

272

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Key Points• MYD88 L265P is a widely expressed somatic mutation in WM patients that supports NF-kB signaling through stimulation of BTK and IRAK 1/4. • Combined suppression of BTK and IRAK in MYD88 L265P expressing WM cells promotes synergistic inhibition of NF-kB signaling and WM cell killing.Myeloid differentiation factor 88 (MYD88) L265P somatic mutation is highly prevalent in Waldenström macroglobulinemia (WM) and supports malignant growth through nuclear factor kB (NF-kB

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“…To determine whether IRAK1/IRAK4 signaling contributes to T-ALL proliferation, we inhibited IRAK1/4 activity using a small-molecule inhibitor that selectively inhibits the kinase activities of IRAK1 and IRAK4 (37). As shown in Figure 2A, IRAK1/4 inhibition significantly impaired the proliferation of 8 of 10 malignant T cell lines in a concentration-dependent manner.…”

Section: Irak1/4 Signaling Inhibition Impedes T-all Proliferationmentioning

confidence: 99%

Inhibition of IRAK1/4 sensitizes T cell acute lymphoblastic leukemia to chemotherapies

Li¹,

Younger²,

Gartenhaus³

et al. 2015

J. Clin. Invest.

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Discovery and initial SAR of inhibitors of interleukin-1 receptor-associated kinase-4

Cited by 108 publications

References 9 publications

Mouse Bone Marrow Sca-1 ⁺ CD44 ⁺ Mesenchymal Stem Cells Kill Avirulent Mycobacteria but Not Mycobacterium tuberculosis through Modulation of Cathelicidin Expression via the p38 Mitogen-Activated Protein Kinase-Dependent Pathway

Mouse Bone Marrow Sca-1 ⁺ CD44 ⁺ Mesenchymal Stem Cells Kill Avirulent Mycobacteria but Not Mycobacterium tuberculosis through Modulation of Cathelicidin Expression via the p38 Mitogen-Activated Protein Kinase-Dependent Pathway

A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenström macroglobulinemia

Inhibition of IRAK1/4 sensitizes T cell acute lymphoblastic leukemia to chemotherapies

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Discovery and initial SAR of inhibitors of interleukin-1 receptor-associated kinase-4

Cited by 108 publications

References 9 publications

Mouse Bone Marrow Sca-1 + CD44 + Mesenchymal Stem Cells Kill Avirulent Mycobacteria but Not Mycobacterium tuberculosis through Modulation of Cathelicidin Expression via the p38 Mitogen-Activated Protein Kinase-Dependent Pathway

Mouse Bone Marrow Sca-1 + CD44 + Mesenchymal Stem Cells Kill Avirulent Mycobacteria but Not Mycobacterium tuberculosis through Modulation of Cathelicidin Expression via the p38 Mitogen-Activated Protein Kinase-Dependent Pathway

A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenström macroglobulinemia

Inhibition of IRAK1/4 sensitizes T cell acute lymphoblastic leukemia to chemotherapies

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Mouse Bone Marrow Sca-1 ⁺ CD44 ⁺ Mesenchymal Stem Cells Kill Avirulent Mycobacteria but Not Mycobacterium tuberculosis through Modulation of Cathelicidin Expression via the p38 Mitogen-Activated Protein Kinase-Dependent Pathway

Mouse Bone Marrow Sca-1 ⁺ CD44 ⁺ Mesenchymal Stem Cells Kill Avirulent Mycobacteria but Not Mycobacterium tuberculosis through Modulation of Cathelicidin Expression via the p38 Mitogen-Activated Protein Kinase-Dependent Pathway