Presentation: “Fanning the Flames: Inflammasome-regulated IL-22BP controls colon tumorigenesis”
Presenter: Jenny Qi, second-year BMS student
Paper: Huber, S. et al. IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine, Nature, 2012 Oct 17.
In a nutshell:
It’s well documented that chronic inflammation increases the risk of cancer. This can be explained by the concept that tumors are just wounds that don’t heal, and the same inflammatory and growth-promoting factors and pathways responsible for wound healing are hijacked to form a tumor.
One of the specific factors is the cytokine IL-22, which is secreted by immune cells to promote inflammation and epithelial cell proliferation. While necessary to heal a wound, these processes can lead to formation of a tumor if they’re not shut off. Luckily, IL-22BP or IL-22 binding protein can neutralize IL-22 to prevent this. Supporting this idea is the observation that IL-22BP decreases during wound healing, perhaps to allow for an increase in IL-22 activity. Little else, however, is known about IL-22BP, so the authors wanted to investigate what BP is doing and how it is regulated.
First, the authors fed mice a chemical called dextran sodium sulfate (DSS) to induce wounds in their colons. They looked at mRNA levels and saw that il22bp expression was lowest at the peak of disease, and il22 was highest. When the wound healed and the mice recovered, il22bp increased again and il22 decreased. The expression levels were inversely correlated. Knockout mice lacking IL-22BP altogether had increased tumors. All of this supports the idea that IL-22BP is necessary to inhibit tumor development, possibly by inhibiting the activities of IL-22, specifically cell proliferation.
The authors then wanted to learn more about the regulation of IL-22BP. They found that the protein is expressed in a subset of CD11c+ immune cells (probably dendritic cells, which help combine the different branches of our immune system). They then also tested a few of the specific pathways involved in regulating IL-22BP by knocking out certain components and seeing if there was a change in IL-22BP expression.
In wild-type mice, there was massive down-regulation of IL-22BP during wound healing. Mice lacking microbes, accomplished by antibiotic treatment, could not down-regulate IL-22BP completely. Microbial products can activate various inflammatory pathways. The authors found that the inflammasome was the pathway important in this situation — mice lacking any component of this complex could not down-regulate IL-22BP. This all indicates that IL-22BP regulation depends on microbes and inflammasome activity.
The authors concluded that IL-22BP is important in normal wound healing and also a possible tumor-inhibiting factor, and that IL-22BP is regulated by microbiota and inflammasome activation, both hot topics in biology today. On a larger scale, we’re left with some important questions: Can we use IL-22BP therapeutically to slow tumor growth? And how do microbes and antibiotics affect cancer progression in patients?
