Toll-like receptor-7 tolerizes malignant B cells and enhances killing by cytotoxic agents.

Cancer Res

Division of Molecular and Cellular Biology, Research Institute, Sunnybrook Health Sciences Center, 2075 Bayview Avenue, Toronto, Ontario, Canada.

Published: February 2007

Chronic activation through Toll-like receptors (TLR) occurs in a number of pathologic settings, but has not been studied to the same extent as primary activation. TLR7, expressed by B cells and some dendritic cells, recognizes molecular patterns associated with viruses that can be mimicked by synthetic imidazoquinolines. In response to primary stimulation with the imidazoquinoline, S28690, human mononuclear cells produced tumor necrosis factor-alpha, but were unable to do so upon restimulation with S28690. This state of "tolerization" lasted at least 5 days. Using chronic lymphocytic leukemia B cells as a model to facilitate biochemical analysis, the tolerized state was found to be associated with altered receptor components, including down-regulated expression of TLR7 mRNA and decreased levels of interleukin-1 receptor-associated kinase 1. Tolerization was characterized by a transcriptionally regulated block in stress-activated protein kinase and nuclear factor kappaB activation, with relatively preserved activation of extracellular signal-regulated kinase (ERK). Tolerized chronic lymphocytic leukemia cells were found to be more sensitive to cytotoxic chemotherapeutic agents, in part through altered stress-activated protein kinase signaling pathways. This property of the TLR7-tolerized state may potentially be exploited in the treatment of B cell cancers.

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-06-2381DOI Listing

Publication Analysis

Top Keywords

chronic lymphocytic
8
lymphocytic leukemia
8
leukemia cells
8
stress-activated protein
8
protein kinase
8
cells
6
toll-like receptor-7
4
receptor-7 tolerizes
4
tolerizes malignant
4
malignant cells
4

Similar Publications

Background: Programmed cell death 1 (PD-1) signaling blockade by immune checkpoint inhibitors (ICI) effectively restores immune surveillance to treat melanoma. However, chronic interferon-gamma (IFNγ)-induced immune homeostatic responses in melanoma cells contribute to immune evasion and acquired resistance to ICI. Poly ADP ribosyl polymerase 14 (PARP14), an IFNγ-responsive gene product, partially mediates IFNγ-driven resistance.

View Article and Find Full Text PDF

Despite viral suppression with antiretroviral therapy, immune nonresponders (INR) among people living with HIV (PLWH) still have a higher risk of developing AIDS-related and non-AIDS-related complications. Our study aimed to investigate the phenotype and functions of Natural Killer (NK) cells in INR, to better understand underlying mechanisms of immune nonresponse. Our cross-sectional study included PLWH aged over 45 with an undetectable HIV viral load sustained for at least 2 years.

View Article and Find Full Text PDF

Background: Bone marrow inflammaging is a low-grade chronic inflammation that induces bone marrow aging. Multiple age-related and inflammatory diseases involve bone marrow inflammaging. Whether common pathological pathways exist in bone marrow inflammaging remains unclear.

View Article and Find Full Text PDF

Purpose: The C-reactive protein (CRP)-albumin-lymphocyte (CALLY) index is a newly developed biomarker that combines measurements of CRP, serum albumin, and lymphocyte count. This index provides a thorough assessment of a patient's inflammation level, nutritional condition, and immunological function. The objective of this study is to examine the correlation between the CALLY index and all-cause mortality in COPD patients.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!