New Methods to Decrease Inflammation, Discover, Researchers Discover

Researchers at the UT Southwestern have discovered two proteins that diminish a possibly life-threatening immune reaction to lingering infections.

The proteins, which are known as SIX1 and SIX2, stimulate the cellular paths needed for development of a fetus and then shift to a role where they suppress these paths in cells of the adult immune system.

“This work provides insight into the molecular components required to limit tissue damage associated with uncontrolled inflammation, such as in septic shock, and reveals how cancer cells may suppress the innate immune system during tumor genesis,” stated Dr. Neal Alto. He is the Professor of Microbiology at UT Southwestern and also co-author of the study.

Proteins that bind to special sections of the DNA to activate or suppress the gene are known as transcription factors. “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,” Dr. Alto stated. He holds the Lorraine Sulkin Schein Endowed Distinguished Professorship in Microbial Pathogenesis.

The researchers saw that the proteins seemed to dampen the immune response of the body to avert damage related to a possibly life-threatening illness, a cytokine storm, which may arise in lingering inflammatory conditions. “A cytokine storm can occur when the body’s immune cells and activators (cytokines) show an overresponse to a health threat such as the flu,” he elaborated.

A mouse model discovered that expression of SIX1 in adulthood granted almost full recovery after subject to a toxin that can initiate a cytokine storm. The proteins appear to diminish the response of the noncanonical NF-κB path, a signaling cascade necessary in the formation of lymph organs, the maturation of the B cells, and the growth of bone cells.

The group also found that cancer cells from patients with treatment-resistant lung cancer showed increased levels of the two proteins. Scientists used the CRISPR-Cas9 gene-editing technology to eliminate the genes producing those two proteins, thus making cancer cells more sensitive to a drug group-SMAC mimetics.

“These findings indicate that disruption of this pathway could have important consequences for the pathogenesis of human disease, including cancer,” he told.