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Describing a Transcription Factor Dependent Regulation of the MicroRNA Transcriptome
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Microenvironmental interleukin-6 suppresses toll-like receptor signaling in human leukemia cells through miR-17/19A

Yanmei Li1, Yonghong Shi1, Lindsay McCaw1

  • 1Biology Platform, Sunnybrook Research Institute, Toronto, Canada;

Blood
|June 5, 2015
PubMed

Insights

Interleukin-6 (IL-6) can suppress chronic lymphocytic leukemia (CLL) growth by inhibiting toll-like receptor (TLR) signaling. This involves microRNAs targeting TLR7 and TNF-α, creating a tolerance that IL-6 blockade can reverse.

Area of Science:

  • Immunology
  • Cancer Biology
  • Molecular Biology

Background:

  • Toll-like receptor (TLR) signaling in the tumor microenvironment is crucial for cancer biology but poorly understood.
  • Chronic lymphocytic leukemia (CLL) cells exhibit specific responses to TLR agonists.

Purpose of the Study:

  • To investigate the regulation of TLR7 signaling in CLL cells within a tumor microenvironment.
  • To identify factors contributing to TLR7 agonist tolerance in CLL.

Main Methods:

  • Studied TLR7 responses of CLL cells with and without a human leukemic spleen stromal cell line.
  • Analyzed the role of interleukin-6 (IL-6) and microRNAs (miR-17, miR-19a) in regulating TLR7 signaling.
  • Utilized antagomiRs, IL-6 inhibition (antibodies, JAK inhibitors), and in vitro/in vivo models (NOD-SCIDγc mice).

Main Results:

  • CLL cells produced high levels of tumor necrosis factor (TNF)-α and proliferated upon TLR7-agonist stimulation.
  • IL-6 upregulated miR-17 and miR-19a, targeting TLR7 and TNF-α mRNA, inducing tolerance to TLR7 agonists.
  • Inhibition of IL-6 signaling reversed tolerance, increasing TLR7-stimulated CLL cell proliferation in vitro and in vivo.

Conclusions:

  • IL-6, via miR-17/19a, induces tolerance to TLR7 agonists in CLL cells.
  • IL-6 signaling inhibition restores TLR7-mediated anti-leukemic responses.
  • IL-6 may function as a tumor suppressor in CLL by inhibiting TLR signaling.

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