Cytokine Identified That Causes Mucositis in Cancer Therapy Patients

The mucosal lining of the mouth becomes thin, may slough off, and then become red, inflamed, and ulcerated. Ulcers may range from 0.5 centimeters to greater than four centimeters. Oral mucositis can be severely painful with the degree of pain usually related to the extent of the tissue damage. Due to pain, the patient may experience trouble speaking, eating, or even opening the mouth. Mucositis is often a major reason for premature suspension of anticancer therapy.

To study the molecular mechanisms responsible for mucositis investigators at the Hebrew University of Jerusalem (Israel) genetically engineered a line of mice to lack the gene that encodes the enzyme E3 beta-TrCP (beta-transducin repeat containing E3 ubiquitin protein ligase) in their gut epithelium. Deletion of beta-TrCP in the gut deregulated the cell cycle, induced a DNA damage response (DDR), and abolished the epithelium barrier function, resulting in a lethal mucosal inflammation that mimicked human mucositis.

Examination of these animals at the molecular level revealed that epithelial-derived IL-1beta, likely induced by DDR independently of NF-kappaB, was a major culprit, and initiated the pathology by compromising epithelial tight junctions. IL-1beta is a member of the interleukin 1 family of cytokines. This cytokine is produced by activated macrophages as a proprotein, which is proteolytically processed to its active form by caspase 1. This cytokine is an important mediator of the inflammatory response, and is involved in a variety of cellular activities, including cell proliferation, differentiation, and apoptosis. The induction of cyclooxygenase-2 by this cytokine in the central nervous system was found to contribute to inflammatory pain hypersensitivity.

The investigators reported in the January 27, 2013, online edition of the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS) that antibody neutralization of IL-1beta prevented epithelial tight junction dysfunction and alleviated mucositis in beta-TrCP–deficient mice. They suggested that IL-1beta antagonists should be considered for prevention and treatment of mucositis.

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Hebrew University of Jerusalem