scholarly journals Thymic Stromal Lymphopoietin Interferes with the Apoptosis of Human Skin Mast Cells by a Dual Strategy Involving STAT5/Mcl-1 and JNK/Bcl-xL

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 829 ◽  
Author(s):  
Tarek Hazzan ◽  
Jürgen Eberle ◽  
Margitta Worm ◽  
Magda Babina
Keyword(s):  
Mast Cells ◽  
Myeloid Cell ◽  
B Cell Lymphoma ◽  
Thymic Stromal Lymphopoietin ◽  
Potential Contribution ◽  
Apoptosis Resistance ◽  
Distinct Component ◽  
Inflammatory Reactions ◽  
Dual Strategy ◽  
High Level

Mast cells (MCs) play critical roles in allergic and inflammatory reactions and contribute to multiple pathologies in the skin, in which they show increased numbers, which frequently correlates with severity. It remains ill-defined how MC accumulation is established by the cutaneous microenvironment, in part because research on human MCs rarely employs MCs matured in the tissue, and extrapolations from other MC subsets have limitations, considering the high level of MC heterogeneity. Thymic stromal lymphopoietin (TSLP)—released by epithelial cells, like keratinocytes, following disturbed homeostasis and inflammation—has attracted much attention, but its impact on skin MCs remains undefined, despite the vast expression of the TSLP receptor by these cells. Using several methods, each detecting a distinct component of the apoptotic process (membrane alterations, DNA degradation, and caspase-3 activity), our study pinpoints TSLP as a novel survival factor of dermal MCs. TSLP confers apoptosis resistance via concomitant activation of the TSLP/ signal transducer and activator of transcription (STAT)-5 / myeloid cell leukemia (Mcl)-1 route and a newly uncovered TSLP/ c-Jun-N-terminal kinase (JNK)/ B-cell lymphoma (Bcl)-xL axis, as evidenced by RNA interference and pharmacological inhibition. Our findings highlight the potential contribution of TSLP to the MC supportive niche of the skin and, vice versa, highlight MCs as crucial responders to TSLP in the context of TSLP-driven disorders.

Phenethyl isothiocyanate decreases thymic stromal lymphopoietin-induced inflammatory reactions in mast cells

2017 ◽  
Vol 42 (1) ◽  
pp. e12449
Author(s):  
Na-Ra Han ◽  
Phil-Dong Moon ◽  
Ka-Jung Ryu ◽  
Hyung-Min Kim ◽  
Hyun-Ja Jeong
Keyword(s):  
Mast Cells ◽  
Thymic Stromal Lymphopoietin ◽  
Phenethyl Isothiocyanate ◽  
Inflammatory Reactions

scholarly journals IRE1 Alpha/XBP1 Axis Sustains Primary Effusion Lymphoma Cell Survival by Promoting Cytokine Release and STAT3 Activation

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 118
Author(s):  
Roberta Gonnella ◽  
Maria Saveria Gilardini Montani ◽  
Luisa Guttieri ◽  
Maria Anele Romeo ◽  
Roberta Santarelli ◽  
...  
Keyword(s):  
Primary Effusion Lymphoma ◽  
B Cell Lymphoma ◽  
Vascular Endothelial ◽  
Unfolded Protein ◽  
Oncogenic Pathways ◽  
Activating Transcription Factor ◽  
High Level ◽  
Protein Response ◽  
Endothelial Growth Factor ◽  
Constitutive Phosphorylation

Primary Effusion Lymphoma (PEL) is a highly aggressive B cell lymphoma associated with Kaposi’s Sarcoma-associated Herpesvirus (KSHV). It is characterized by a high level of basal Endoplasmic Reticulum (ER) stress, Unfolded Protein Response (UPR) activation and constitutive phosphorylation of oncogenic pathways such as the Signal Transducer and activator of Transcription (STAT3). In this study, we found that the inositol requiring kinase (IRE) 1alpha/X-box binding protein (XBP1) axis of UPR plays a key role in the survival of PEL cells, while double stranded RNA-activated protein kinase-like ER kinase (PERK) and activating transcription factor (ATF) 6 slightly influence it, in correlation with the capacity of the IRE1alpha/XBP1 axis to induce the release of interleukin (IL)-6, IL-10 and Vascular-Endothelial Growth Factor (VEGF). Moreover, we found that IRE1alpha/XBP1 inhibition reduced STAT3 Tyr705 phosphorylation and induced a pro-survival autophagy in PEL cells. In conclusion, this study suggests that targeting the IRE1alpha/XBP1 axis represents a promising strategy against PEL cells and that the cytotoxic effect of this treatment may be potentiated by autophagy inhibition.

scholarly journals Thymic Stromal Lymphopoietin Promotes MRGPRX2-Triggered Degranulation of Skin Mast Cells in a STAT5-Dependent Manner with Further Support from JNK

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 102
Author(s):  
Magda Babina ◽  
Zhao Wang ◽  
Kristin Franke ◽  
Torsten Zuberbier
Keyword(s):  
Mast Cells ◽  
Priming Effect ◽  
Skin Diseases ◽  
Thymic Stromal Lymphopoietin ◽  
Dependent Manner ◽  
Atopic Diseases ◽  
Time Points ◽  
Histamine Liberation ◽  
Atopic Skin ◽  
Th2 Immunity

Thymic stromal lymphopoietin (TSLP) is released by epithelial cells following disturbed homeostasis to act as “alarmin” and driver of Th2-immunity. Aberrant TSLP expression is a hallmark of atopic diseases, including atopic dermatitis (AD). Mast cells (MCs) are overabundant in AD lesions and show signs of degranulation, but it remains unknown whether TSLP contributes to granule discharge. Degranulation of skin MCs proceeds via two major routes, i.e., FcεRI-dependent (allergic) and MRGPRX2-mediated (pseudo-allergic/neurogenic). Evidence is accumulating that MRGPRX2 may be crucial in the context of skin diseases, including eczema. The current study reveals TSLP as a novel priming factor of human skin MCs. Interestingly, TSLP selectively cooperates with MRGPRX2 to support granule discharge, while it does not impact spontaneous or FcεRI-driven exocytosis. TSLP-assisted histamine liberation triggered by compound 48/80 or Substance P, two canonical MRGPRX2 agonists, was accompanied by an increase in CD107a+ cells (a MC activation marker). The latter process was less potent, however, and detectable only at the later of two time points, suggesting TSLP may prolong opening of the granules. Mechanistically, TSLP elicited phosphorylation of STAT5 and JNK in skin MCs and the reinforced degranulation critically depended on STAT5 activity, while JNK had a contributory role. Results from pharmacological inhibition were confirmed by RNA-interference, whereby silencing of STAT5 completely abolished the priming effect of TSLP on MRGPRX2-mediated degranulation. Collectively, TSLP is the first factor to favor MRGPRX2- over FcεRI-triggered MC activation. The relevance of TSLP, MCs and MRGPRX2 to pruritis and atopic skin pathology indicates broad repercussions of the identified connection.

scholarly journals Targeted inhibition of PI3Kα/δ is synergistic with BCL-2 blockade in genetically defined subtypes of DLBCL

Blood ◽  
2019 ◽  
Vol 133 (1) ◽  
pp. 70-80 ◽  
Author(s):  
Kamil Bojarczuk ◽  
Kirsty Wienand ◽  
Jeremy A. Ryan ◽  
Linfeng Chen ◽  
Mariana Villalobos-Ortiz ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Xenograft Model ◽  
Myeloid Cell ◽  
B Cell Lymphoma ◽  
Cell Receptor ◽  
Synergistic Activity ◽  
Genetic Bases

Abstract Inhibition of the B-cell receptor (BCR) signaling pathway is a promising treatment strategy in multiple B-cell malignancies. However, the role of BCR blockade in diffuse large B-cell lymphoma (DLBCL) remains undefined. We recently characterized primary DLBCL subsets with distinct genetic bases for perturbed BCR/phosphoinositide 3-kinase (PI3K) signaling and dysregulated B-cell lymphoma 2 (BCL-2) expression. Herein, we explore the activity of PI3K inhibitors and BCL-2 blockade in a panel of functionally and genetically characterized DLBCL cell line models. A PI3K inhibitor with predominant α/δ activity, copanlisib, exhibited the highest cytotoxicity in all BCR-dependent DLBCLs. The proapoptotic effect of copanlisib was associated with DLBCL subtype-specific dysregulated expression of BCL-2 family members including harakiri (HRK) and its antiapoptotic partner BCL extra large (BCL-xL), BCL2 related protein A1, myeloid cell leukemia 1 (MCL-1), and BCL2 interacting mediator of cell death. Using functional BH3 profiling, we found that the cytotoxic activity of copanlisib was primarily mediated through BCL-xL and MCL-1–dependent mechanisms that might complement BCL-2 blockade. For these reasons, we evaluated single-agent activity of venetoclax in the DLBCLs and identified a subset with limited sensitivity to BCL-2 blockade despite having genetic bases of BCL-2 dysregulation. As these were largely BCR-dependent DLBCLs, we hypothesized that combined inhibition of PI3Kα/δ and BCL-2 would perturb BCR-dependent and BCL-2–mediated survival pathways. Indeed, we observed synergistic activity of copanlisib/venetoclax in BCR-dependent DLBCLs with genetic bases for BCL-2 dysregulation in vitro and confirmed these findings in a xenograft model. These results provide preclinical evidence for the rational combination of PI3Kα/δ and BCL-2 blockade in genetically defined DLBCLs.

scholarly journals Thymic stromal lymphopoietin is released by human epithelial cells in response to microbes, trauma, or inflammation and potently activates mast cells

2007 ◽  
Vol 204 (2) ◽  
pp. 253-258 ◽  
Author(s):  
Zoulfia Allakhverdi ◽  
Michael R. Comeau ◽  
Heidi K. Jessup ◽  
Bo-Rin Park Yoon ◽  
Avery Brewer ◽  
...  
Keyword(s):  
Mast Cells ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Immunoglobulin E ◽  
Interleukin 1 ◽  
Allergic Inflammation ◽  
Thymic Stromal Lymphopoietin ◽  
Microbial Products ◽  
Necrosis Factor

Compelling evidence suggests that the epithelial cell–derived cytokine thymic stromal lymphopoietin (TSLP) may initiate asthma or atopic dermatitis through a dendritic cell–mediated T helper (Th)2 response. Here, we describe how TSLP might initiate and aggravate allergic inflammation in the absence of T lymphocytes and immunoglobulin E antibodies via the innate immune system. We show that TSLP, synergistically with interleukin 1 and tumor necrosis factor, stimulates the production of high levels of Th2 cytokines by human mast cells (MCs). We next report that TSLP is released by primary epithelial cells in response to certain microbial products, physical injury, or inflammatory cytokines. Direct epithelial cell–mediated, TSLP-dependent activation of MCs may play a central role in “intrinsic” forms of atopic diseases and explain the aggravating role of infection and scratching in these diseases.

scholarly journals Hematopoietic Cell Fate and the Initiation of Leukemic Properties in Primitive Primary Human Cells Are Influenced by Ras Activity and Farnesyltransferase Inhibition

2004 ◽  
Vol 24 (16) ◽  
pp. 6993-7002 ◽  
Author(s):  
Craig Dorrell ◽  
Katsuto Takenaka ◽  
Mark D. Minden ◽  
Robert G. Hawley ◽  
John E. Dick
Keyword(s):  
Cell Fate ◽  
Myeloid Cell ◽  
Early Event ◽  
Ras Signaling ◽  
Human Leukemia ◽  
Ras Pathway ◽  
Hematopoietic Malignancies ◽  
Ras Activation ◽  
Elevated Frequency ◽  
High Level

ABSTRACT The Ras pathway transduces divergent signals determining normal cell fate and is frequently activated in hematopoietic malignancies, but the manner in which activation contributes to human leukemia is poorly understood. We report that a high level of activated H-Ras signaling in transduced primary human hematopoietic progenitors reduced their proliferation and enhanced monocyte/macrophage differentiation. However, the exposure of these cells to a farnesyltransferase inhibitor and establishment of a moderate level of Ras activity showed increased proliferation, an elevated frequency of primitive blast-like cells, and progenitors with enhanced self-renewal capacity. These results suggest that the amplitude of Ras pathway signaling is a determinant of myeloid cell fate and that moderate Ras activation in primitive hematopoietic cells can be an early event in leukemogenesis.

Sign in / Sign up

Export Citation Format

Share Document