A common protein found throughout the body, NF-kB, promotes harmful inflammation, cell proliferation and cell death in the intestinal lining, the key features of inflammatory bowel disease (IBD), according to research recently published in The Journal of Pathology.
“This was surprising because usually NF-kB helps protect cells from death,” says Dr. Marina Kolesnichenko. The scientist from the Signal Transduction in Tumour Cells Lab spearheaded the research at Max Delbrück Centre for Molecular Medicine in the Helmholtz Association (MDC).
Good or bad?
NF-kB is a family of transcription factor proteins, which transcribe parts of DNA inside cells to carry out various cellular processes, from cell replication and survival, to inflammation and cell death, which is called apoptosis.
NF-kB’s role in apoptosis in the intestine has been up for debate, with some studies suggesting it plays a protective or “anti-apoptotic” role, while others found hints it might be “pro-apoptotic,” contributing to cell death. One reason for the lack of clarity: previous studies mostly disrupted the signaling pathway several steps “upstream”, this means before NF-kB gets activated, rather than targeting NF-kB directly.
A specific target
Normally, NF-kB can’t begin its work until it is released by an inhibiting molecule. Kolesnichenko and her collaborators developed a mouse model that blocks the inhibitor specifically in the epithelium, which are the cells lining the gut. This unleashed persistent NF-kB activation only in that tissue. Extended activation in the intestinal lining was distinctly harmful, leading to increased inflammation in both the intestine and colon, as well as dangerous stem cell hyperproliferation and cell death in the intestine.
“The study demonstrates that activation of NF-kB alone, without any contribution of upstream components, is sufficient to trigger an IBD-like pathology,” says Prof. Claus Scheidereit, who heads the Signal Transduction in Tumour Cells Lab.
The team further investigated the results in epithelial organoids, which are miniature guts cultured from the intestinal linings of the modified mice. The researchers found that without immune cells present, activated NF-kB boosted abnormal signaling of the Wnt pathway. Aberrant Wnt signaling is detected in the majority of cases of colorectal cancer.
Given that IBD patients are at higher risk of developing colorectal cancer later in life, Kolesnichenko is curious to investigate if NF-kB is a key driver of that transition towards cancer. Further investigations might reveal that blocking NF-kB in the intestinal lining could help treat IBD or colorectal cancer.
A unique position
Kolesnichenko initiated and led the study, collaborating with several women from other units at MDC and at Charité – Universitätsmedizin Berlin. Notably, she published the results as the senior paper author, which is unusual for MDC post docs. Kolesnichenko notes it is important for post docs to be able to show independence and initiative, particularly when seeking funding from agencies that consider the number of “last author” papers they have published.
“The most rewarding part was working together with truly inspiring scientists, each of whom contributed something unique and essential to the story,” Kolesnichenko says.
Text: Laura Petersen
Nadine Mikuda et al. (2020): "Deficiency in IκBα in the intestinal epithelium leads to spontaneous inflammation and mediates apoptosis in the gut", The Journal of Pathology, DOI: