Failure to Inactivate NF-kappaB Leads to Chronic Inflammation and Immune Disorders

New insights into how NF-kappaB signaling is regulated may lead to development of more effective drugs for controlling inflammation and reducing chronic immune responses.

NF-kappaB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that controls the transcription of DNA. As such, it is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens. NF-kappaB plays a key role in regulating the immune response to infection, and incorrect regulation of NF-kappaB has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection, and improper immune development.

Investigators at the Tokyo Institute of Technology (Japan) and the Weizmann Institute of Science (Rehovot, Israel) recently released results from experiments designed to explain the interaction of molecular factors related to regulation of NF-kappaB.

They reported in the October 25, 2012, issue of the journal Cell Reports that NF-kappaB activity was to a major extent controlled by the protein DSIF (DRB sensitivity inducing factor). This finding emerged from experiments utilizing cells where DSIF activity had been blocked. In these cells, a negative feedback loop failed to function and NF-kappaB activity remained high following stimulation, while similar activity in normal cells returned to background levels in a short period of time. Persistent activation of NF-kappaB can lead to various pathogenic conditions such as chronic inflammation, autoimmune diseases, and cancer.

Commenting on their findings, the authors said, “The unique control of the negative feedback regulator genes by DSIF may be utilized by cells under circumstances in which prolonged NF-kappaB activity is needed.”

Future studies will focus on DSIF under specific settings that should aid in identifying drug targets for selective manipulation of NF-kappaB activity.

Related Links:
Tokyo Institute of Technology
Weizmann Institute of Science