Src-kinase inhibitors sensitize human cells of myeloid origin to Toll-like-receptor–induced interleukin 12 synthesis

Wölfl, Matthias; Schwinn, Stefanie; Yoo, Youngeun; Reß, Marie L.; Braun, Matthias; Chopra, Martin; Schreiber, S.; Ayala, Victor I.; Öhlén, Claes; Eyrich, Matthias; Beilhack, Andreas; Schlegel, Paul G.

doi:10.1182/blood-2013-03-488072

Cited by 18 publications

(15 citation statements)

References 45 publications

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“…Src-kinase inhibitors dasatinib hold great potential as targeted therapy against malignant cells and dasatinib could increase TLR–induced interleukin 12 production in human myeloid cells 36 . Then to further confirm the role of Src in the inflammatory conditions, we investigated function of dasatinib in DSS induced colitis.…”

Section: Resultsmentioning

confidence: 99%

Integrin CD11b attenuates colitis by strengthening Src-Akt pathway to polarize anti-inflammatory IL-10 expression

Han

Jin

et al. 2016

Sci Rep

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Interleukin-10 (IL-10) plays a central role in regulation of intestinal mucosal homeostasis and prevention of inflammatory bowel disease (IBD). We previously reported that CD11bhi regulatory dendritic cells (DCs) can produce more IL-10, and CD11b can negatively regulate Toll-like receptors (TLRs)-induced inflammatory responses in macrophages. However whether CD11b and its signaling can control autoimmunity via IL-10 production remains unclear. Here we found that CD11b deficient (Itgam−/−) mice were more susceptible to dextran sulfate sodium (DSS)-induced colitis, with more tumor necrosis factor α (TNF-α) while less IL-10 production. CD11b inhibited nuclear factor-kappa B (NF-κB) while promoted activator protein 1 (AP-1) activation through activating sarcoma oncogene (Src), leading to decreased TNF-α while increased IL-10 production. Src interacted with and promoted c-casitas B lineage lymphoma proto-oncogene (c-Cbl)-mediated degradation of the inhibitory subunit p85 of phosphatidylinositol 3-kinase (PI3K). Importantly, Src inhibitor dasatinib aggravated DSS-induced colitis by decreasing IL-10 while increasing TNF-α in vivo. Therefore, CD11b promotes IL-10 production by activating Src-Akt signal pathway. An axis of CD11b-Src pathway is important in balancing homeostasis of TLR-induced pro-inflammatory and anti-inflammatory responses.

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Section: Resultsmentioning

confidence: 99%

Integrin CD11b attenuates colitis by strengthening Src-Akt pathway to polarize anti-inflammatory IL-10 expression

Han

Jin

et al. 2016

Sci Rep

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“…Tyrosine kinases also shape innate immune responses by interfering with Toll like receptor signaling, phagocytosis and the maturation of monocytes possibly by the up‐regulation of the inhibitory receptor osteoactivin . Accordingly, TKIs have multiple effects on the function of myeloid cells, including myelopoiesis , cytokine release , migration of dendritic cells , inflammation and related tissue damage , autophagy , lysosomal acidification and antimicrobial activity . Considering the diverse functions controlled by Abl/Src kinases it is unexpected, that severe infections related to TKI‐treatment are exceptional .…”

Section: Discussionmentioning

confidence: 99%

The tyrosine kinase inhibitor dasatinib reduces the growth of intracellular Mycobacterium tuberculosis despite impairing T‐cell function

et al. 2018

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Tyrosine kinases are checkpoints for multiple cellular pathways and dysregulation induces malignancies, most notably chronic myeloid leukemia (CML). Inhibition of Abltyrosine kinases has evolved as a new concept for the treatment of CML and other malignant diseases. Due to the multiple immune-modulatory pathways controlled by tyrosine kinases, treatment with tyrosine kinase inhibitors (TKIs) will not only affect the biology of malignant cells but also modulate physiological immune functions. To understand the effects of TKIs on host defense against intracellular bacteria, we investigated the immunological impact of the dual Abl/Src TKI dasatinib on the cellular immune response to Mycobacterium tuberculosis (Mtb). Our results demonstrate that dasatinib impaired proliferation, cytokine release (IFN-γ, TNF-α, GM-CSF), expression of granulysin and degranulation of cytotoxic effector molecules of human Mtb-specific T-lymphocytes by inhibition of lymphocyte-specific protein tyrosine kinase (Lck) phosphorylation. Despite this profound inhibition of T-cell function, dasatinib suppressed growth of virulent Mtb in human macrophages co-cultured with autologous Mtb-specific T-cells (49±15%). Functional analysis suggested that growth inhibition is due to dasatinib-triggered lysosomal acidification inMtb-infected macrophages. These results highlight the significance of innate immune responses, i.e. acidification of lysosomes, which control the multiplication of intracellular bacteria despite the lack of efficient T-cell support. Keywords: Human primary cells r infection immunology r infection immunology r tuberculosis r T-cells r Tyrosine kinase inhibitorAdditional supporting information may be found online in the Supporting Information section at the end of the article.

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“…The function of DC is differentially regulated by complex networks of intracellular signaling pathways. [24][25][26][27] Intriguingly, these pathways do not always serve the same function in all subsets of DC. This is well illustrated by the p38 mitogen-activated protein kinase (MAPK) pathway that differentially controls expression of the Th1-polarising cytokine IL-12 from moDC and cDC2.…”

Section: Introductionmentioning

confidence: 99%

Impaired circulating myeloid CD1c+ dendritic cell function in human glioblastoma is restored by p38 inhibition – implications for the next generation of DC vaccines

Adhikaree¹,

Franks²,

Televantos³

et al. 2019

OncoImmunology

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2019) Impaired circulating myeloid CD1c+ dendritic cell function in human glioblastoma is restored by p38 inhibition -implications for the next generation of DC vaccines, OncoImmunology, 8:7, e1593803, ABSTRACT Current treatments for glioblastoma (GBM) have limited efficacy and significant morbidity and therefore new strategies are urgently needed. Dendritic cells have the power to create anti-tumor immune responses. The greater potency of circulating dendritic cells (DC) over laboratory-generated monocytederived DC makes them exciting new immunotherapeutic candidates. To determine the immune status of GBM patients we initially investigated the frequency and function of circulating DC subsets. Furthermore, we tested the therapeutic potential of inhibiting the p38 mitogen-activated protein kinase pathway (p38i) in circulating DC to overcome DC dysfunction.GBM patients (n = 16) had significantly reduced numbers of the major myeloid circulating dendritic cell (cDC2) and plasmacytoid DC vs healthy controls; 1736 vs 4975 (p = 0.028) and 893 vs 2287 cells/mL (P = <0.001) respectively. This inversely correlated with dexamethasone (Dex) dose in a log-linear model, and disease status. Patients' cDC2 were immature with impaired interleukin (IL)-12 secretion, reduced IL-12:IL-10 ratio, and low HLA-DR and CD86 expression. Exposure of healthy donor cDC2 to Dex or GBM cell lysate resulted in a similar low IL-12:IL-10 ratio. Inhibition of p38 restored the IL-12:IL-10 balance in Dex or tumor lysate-conditioned healthy cDC2 and enhanced T-cell proliferation and interferon-gamma (IFNγ) production. Importantly, patient-derived cDC2 showed a similar reversal of DC dysfunction with p38i. This study demonstrates the therapeutic potential of developing the next generation of DC vaccines using enhanced p38i-conditioned cDC2. We will therefore shortly embark on a clinical trial of adoptively transferred, p38 MAPKinhibited cDC2 in adults with GBM. ARTICLE HISTORY

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Src-kinase inhibitors sensitize human cells of myeloid origin to Toll-like-receptor–induced interleukin 12 synthesis

Cited by 18 publications

References 45 publications

Integrin CD11b attenuates colitis by strengthening Src-Akt pathway to polarize anti-inflammatory IL-10 expression

Integrin CD11b attenuates colitis by strengthening Src-Akt pathway to polarize anti-inflammatory IL-10 expression

The tyrosine kinase inhibitor dasatinib reduces the growth of intracellular Mycobacterium tuberculosis despite impairing T‐cell function

Impaired circulating myeloid CD1c+ dendritic cell function in human glioblastoma is restored by p38 inhibition – implications for the next generation of DC vaccines

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