Cytokines, IBD, and colitis-associated cancer

Abstract

Inflammatory bowel diseases (IBDs) are debilitating conditions that result in intestinal damage due to chronic inflammation. In addition, the perpetual state of inflammation predisposes individuals to the development of colitis-associated cancer. Because of the immense immune cell infiltration into colon, cytokines produced by immune cells are major players in the initiation and progression of IBD and colitis-associated cancer. In this review, we will explore the functions of many key cytokines and their roles in IBD and colitis-associated cancer, as well as their influences on the immune system and stromal cells. Finally, we will briefly discuss current therapies and current clinical trials targeting cytokines in IBD.

Figure 1. Inflammation drives IBD and CAC pathogenesis

Cytokines induce extensive inflammation in the colon, which has a negative impact on epithelial cells, resident and recruited immune cells, and stromal cells. Inflammation can cause damage to epithelial cells and activate and recruit immune and stromal cells. This leads to a non-resolving chronic inflammatory situation, and leads to the development of IBD and potentially CAC.

Figure 2. The colitis microenvironment

In IBD, the epithelial layer of the colon suffers damage, increased permeability, and leakage of luminal content (microbes, microbial products, metabolites, etc.), which induces local immune cell activation. The production of cytokines by responding leukocytes causes the recruitment of more leukocytes and therefore more cytokine production, causing a positive feedback loop. Other cell types, such as endothelial cells, fibroblasts, and MSCs are also recruited to the site of inflammation. Endothelial cells create new blood vessels, which directly allow more immune cells to reach the damaged area. Fibroblasts can become activated as well and secrete pro-inflammatory cytokines and proliferate out of control, creating fibrosis. Lastly, MSCs actually have a beneficial role, and attempt to regenerate the damage epithelium and secrete the appropriate cytokines.

Figure 3. The tumor microenvironment

Tumors are a complex and heterogeneous mixture of various cell types that dynamically interact with each other. A multitude of cell types, including endothelial cells, fibroblasts, stem cells, and immune cells get recruited to and support tumor progression, and cytokines are major drivers this process. The uneven distribution of the different cell types creates local environments that are dissimilar from one another, and can act as niches for certain cell types, or program cells differentially. Unlike in IBD, wound-healing processes appears to promote tumorigenesis, while they are beneficial to damaged epithelia in colitis. The heterogeneity of the microenvironment is a major therapeutic hurdle, and understanding how cytokines affect each cell type will be critical to clinical efficacy.