Researchers identify new mechanism to reduce inflammation

UTSW researchers identify new mechanism to reduce inflammation
Dr. Neal Alto. Credit: UT Southwestern

UT Southwestern researchers have identified two proteins that act as gatekeepers to dampen a potentially life-threatening immune response to chronic infection.

The proteins—the SIX1 and SIX2—activate required for and later switch to a new role in which they repress these pathways in adult immune system cells. The findings are published today in Nature.

"This work provides insight into the molecular components required to limit associated with uncontrolled inflammation, such as in septic shock, and reveals how may suppress the innate immune system during tumor genesis," said Dr. Neal Alto, Professor of Microbiology at UT Southwestern and corresponding author of the study.

Transcription factors are proteins that bind to special regions of DNA to turn genes on (activate them) or off (repress them). "One of the surprising findings was that a transcription activator that is essential for the development of tissues and organs has been repurposed as a transcriptional repressor in the immune system. While transcription factors can be used differently in various stages of life, a switch from a transcriptional activator in the fetus to a suppressor in adult immune cells is infrequent," said Dr. Alto, who holds the Lorraine Sulkin Schein Endowed Distinguished Professorship in Microbial Pathogenesis. Dr. Alto is also a UT Southwestern Presidential Scholar and a Rita C. and William P. Clements, Jr. Scholar in Medical Research.

He added that the work provides a new pathway for controlling inflammation, which could be important for developing new drugs. It also might explain how cancer cells develop chemotherapy resistance.

UTSW researchers identify new mechanism to reduce inflammation
Dr. Zixu Liu. Credit: UT Southwestern

The researchers found that the two proteins showed inhibitory activities when bound to genes involved in inflammation. Specifically, SIX1 and SIX2 appeared to dampen the body's to prevent damage associated with a potentially life-threatening condition called a cytokine storm, which can occur in chronic inflammatory conditions. "A cytokine storm can occur when the body's and activators (cytokines) show an overresponse to a health threat such as the flu," he explained.

An experiment with transgenic mice found that expression of SIX1 in adulthood conferred near-complete recovery following exposure to a toxin released by that can set off a cytokine storm. The two SIX proteins seem to dampen the response of the so-called noncanonical NF-κB pathway, a signaling cascade that is instrumental in the development of the lymph organs, the maturation of the immune system's antibody-producing B cells, and the development of bone cells. The same pathway is involved in the body's immune defense in adulthood.

The studies, which initially focused on bacteria and viruses, also shed light on mechanisms of cancer cell resistance to drug treatment, Dr. Alto said.

In one series of experiments, the team found that cancer cells derived from patients with treatment-resistant non- expressed high levels of the SIX1 and SIX2 proteins. The scientists used the CRISPR-Cas9 gene-editing technology to remove the genes that produce those two proteins, making the cancer dramatically more sensitive to a promising drug class called SMAC mimetics.

"In summary, we have established that SIX family transcription factors function as immunological gatekeepers, regulating the activity of inflammatory genes in response to noncanonical NF-κB pathway activation," he said. "These findings indicate that disruption of this pathway could have important consequences for the pathogenesis of human disease, including cancer."


Explore further

Scientists narrow in on cells that drive immune response to cancer

More information: Zixu Liu et al, A NIK–SIX signalling axis controls inflammation by targeted silencing of non-canonical NF-κB, Nature (2019). DOI: 10.1038/s41586-019-1041-6
Journal information: Nature

Citation: Researchers identify new mechanism to reduce inflammation (2019, March 22) retrieved 23 August 2019 from https://medicalxpress.com/news/2019-03-mechanism-inflammation.html
This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without the written permission. The content is provided for information purposes only.
449 shares

Feedback to editors

User comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more