Immune System ‘Double Agent’ Could be New Ally in Cancer Fight


Source: St. Jude Children’s Research Hospital

Summary: Researchers have that an enzyme called TAK1 functions like a “double agent” in the innate immune response, serving as an unexpected regulator of inflammation and cell death.


St. Jude Children’s Research Hospital scientists have discovered that an enzyme called TAK1 functions like a “double agent” in the innate immune response, serving as an unexpected regulator of inflammation and cell death. The findings highlight TAK1 inhibition as a potential cancer treatment. Normally, TAK1 is a kinase known to promote inflammation. But this research team showed that TAK1 can suppress inflammation as well. Working in mouse immune cells called macrophages, they demonstrated that TAK1 plays a pivotal role in restricting inflammation and cell death by blocking spontaneous activation of the NLRP3 inflammasome. The NLRP3 inflammasome is a protein complex that, when activated, helps the innate immune system recognize and mount a rapid defense against bacteria, viruses and other threats. The study findings were published in The Journal of Experimental Medicine.

Innate immune system

First author R.K. Subbarao Malireddi, Ph.D., pictured with Thirumala-Devi Kanneganti, Ph.D., a member of the St. Jude Children’s Research Hospital Department of Immunology. Credit: St. Jude Children’s Research Hospital

Without TAK1, macrophages derived from mouse bone marrow died spontaneously in the laboratory even in the absence of the signals normally required to activate NLRP3. Macrophages with TAK1 did not. But the normal (wild-type) macrophages did die when treated with a TAK1 inhibitor. The consequences of TAK1 deficiency included a biochemical cascade that activated the enzymes RIPK1 and caspase-1. Caspase-1 prompts production of proteins like IL-18 and IL-1β that promote inflammation and cell death via the inflammatory cell-death pathway (pyroptosis). These findings show that TAK1 is a central regulator of NLRP3 inflammasome homeostasis and also adds to the evidence that TAK1 inhibitors may have a role in cancer immune therapy.

Thirumala-Devi Kanneganti Ph.D. said, “This research connects TAK1, the NLRP3 inflammasome and RIPK1, apparently for the first time, advancing our understanding of a number of key pathways.”


More Information: R.K. Subbarao Malireddi et al, “TAK1 restricts spontaneous NLRP3 activation and cell death to control myeloid proliferation”, The Journal of Experimental Medicine (2018). DOI: 10.1084/jem.20171922 


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