The Effects of IL-1 Molecules on the Different Stages of Colon Cancer Development

Interleukin-1 is a major, pro-inflammatory, upstream cytokine that initiates and propagates inflammation.

Interleukin-1α (IL‑1α) has been found mainly in intestinal epithelial cells (IECs), both under homeostatic conditions and during inflammation; whereas Interleukin-1β (IL‑1β) was primarily detected in inflammatory cells upon stimulation. In areas of severe tissue damage, both IL-1α and IL-1β were found in myeloid infiltrating cells. Previously, we showed that IL-1α, mainly from IECs is responsible for the initiation and propagation of acute and chronic colon inflammation. Furthermore, chronic colon inflammation is associated with colorectal cancer (CRC) development and progression.

In this study, we assessed the role of IL-1α and IL-1β in different stages of colon cancer development and carcinogenesis. For this aim, mice deficient in IL-1 molecules were subjected to a two step carcinogen model, where AOM was used as an initiator of carcinogenesis and DSS-induced inflammation, as a promotor. Both IL-1α and IL-1β deficient mice were less susceptible to inflammation; however, it was mainly IL-1β deficiency that conferred tumor protection. Similar results were found when using surgical orthotopic implantation of the mouse colon cancer line. Histological evaluation and FACs analyses found differences in the cellular infiltrate in developing tumors and their microenvironment. For example, less inflammation was observed in IL-1β deficient mice. In contrast, a deficiency in IL-1α led to an inefficient immune response against cancer and thus, increased tumor progression. In this study, we found that IEC-derived and myeloid-derived IL-1α played a differential role in inflammation and cancer progression and invasiveness, whereas IL-1β from myeloid cells served as a promotor of tumor invasiveness by inducing pro-inflammatory molecules and recruiting pro-inflammatory myeloid cells to the site of the tumor.