Studies reveal mechanism to reduce inflammation
Two proteins that act as gatekeepers to dampen a potentially life-threatening immune response to chronic infection have been identified in a study published in Nature. The two proteins, the transcription factors SIX1 and SIX2, activate cellular pathways required for fetal development and later switch to a new role in which they repress these pathways in […]
Two proteins that act as gatekeepers to dampen a potentially life-threatening immune response to chronic infection have been identified in a study published in Nature.
The two proteins, the transcription factors SIX1 and SIX2, activate cellular pathways required for fetal development and later switch to a new role in which they repress these pathways in adult immune system cells.
“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,” a Professor of Microbiology and corresponding author of the study, Dr Neal Alto, said.
Transcription factors are proteins that bind to special regions of DNA to turn genes on (activate them) or off (repress them).
He said: “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.”
He added that the work provides a new pathway for controlling inflammation, which could be important for developing new drugs, adding, “It also might explain how cancer cells develop chemotherapy resistance.”
Dr Alto said the studies, which initially focused on bacteria and viruses, also shed light on mechanisms of cancer cell resistance to drug treatment.
In one series of experiments, the team found that cancer cells derived from patients with treatment-resistant non-small cell lung cancer 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 cells 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,” he also said.