Researchers identify new mechanism to reduce inflammation

Researchers at UT Southwestern have identified two proteins that act as controllers to attenuate a potentially fatal immune response to chronic infection.

The proteins – the transcription factors SIX1 and SIX2 – activate the cellular pathways necessary for the development of the fetus and then switch to a new role in which they repress these pathways in the cells of the immune system of the adult. The results are published today in Nature.

"These works provide information on the molecular components needed to limit tissue damage associated with uncontrolled inflammation, such as septic shock, and reveal how cancer cells can 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 activate (activate) or activate (disable) genes. "One of the surprising discoveries has been that a transcription activator essential for the development of tissues and organs has been converted back into a transcriptional repressor in the immune system, although transcription factors can be used differently at different stages of life. , the passage of a transcriptional activator in the fetus is uncommon in suppressor in adult immune cells, "said Dr. Alto, the Lorraine Sulkin Schein Chair of Distinction in Microbial Pathogenesis. Presidential researcher UT Southwestern and Rita C. and William P. Clements, Jr. researcher in medical research.

He added that the work provides a new way to control inflammation, which could be important for the development of new drugs. This could also explain how cancer cells develop resistance to chemotherapy.

The researchers found that both proteins had inhibitory activities when they were linked to genes involved in inflammation. Specifically, SIX1 and SIX2 appeared to attenuate the body's immune response to prevent the damage associated with a life-threatening disease called a cytokine storm that may occur in chronic inflammatory conditions. "A cytokine storm can occur when the body's immune cells and activators (cytokines) show an excessive response to a health threat such as the flu," he said.

An experiment on transgenic mice has shown that the expression of SIX1 in adulthood confers an almost complete recovery after exposure to a toxin released by a Gram-negative bacterium that can trigger a cytokine storm. Both SIX proteins appear to attenuate the so-called non-canonical NF-κB pathway response, a signaling cascade that plays a key role in the development of lymphatic organs, the maturation of antibody-producing B-cells of the immune system, and the bone cell development. The same pathway is involved in the body's immune defense at adulthood.

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

In a series of experiments, the team discovered that cancer cells derived from treatment-resistant non-small cell lung cancer patients expressed high levels of SIX1 and SIX2 proteins. Scientists have used gene editing technology CRISPR-Cas9 to eliminate the genes that produce these two proteins, making cancer cells much more sensitive to a promising class of drugs called SMAC mimics.

"In summary, we have established that SIX family transcription factors function as immunological controllers regulating the activity of inflammatory genes in response to non-canonical activation of the NF-KB pathway", a- he declared. "These results indicate that disruption of this pathway could have significant consequences on the pathogenesis of human diseases, including cancer."

Provided by
UT Southwestern Medical Center