Defining mechanisms of action of interleukin-11 on the progression of radiation-induced oral mucositis in hamsters

Abstract

Oral ulcerative mucositis is a common toxicity associated with drug and radiation therapy for cancer. It impacts on quality of life and economic outcomes, as well as morbidity and mortality. Mucositis is often associated with dose limitations for chemotherapy or is a cause for dose interruption for radiation. The complexity of mucositis as a biological process has only been recently appreciated. It has been suggested that the condition represents a sequential interaction of oral mucosal cells and tissues, pro-inflammatory cytokines and local factors such as saliva and the oral microbiota. The recognition that the pathophysiology of mucositis is a multifactorial process was partially suggested by the observation that interleukin-11 (IL-11), a pleotropic cytokine, favorably altered the course of chemotherapy-induced mucositis in an animal model. In the current study, we evaluated a series of biologic and morphologic outcomes to determine their roles and sequence in the development of experimental radiation-induced mucositis and to evaluate the effects of IL-11 in attenuating them. Our results suggest that IL-11 favorably modulates acute radiation-induced mucositis by attenuating pro-inflammatory cytokine expression. Data are also presented which help define the pathobiological sequence of mucositis.

Introduction

Oral mucositis is a common and painful toxicity experienced by patients receiving radiation therapy for the treatment of head and neck cancer [1]. Not only are the lesions terribly symptomatic, but they are often of such severity as to require breaks in therapy, intravenous fluid support or the need for parenteral nutrition. Despite the clinical significance of mucositis, there is no predictable way to effectively prevent or treat the condition.

It has been generally taken for granted that the pathogenesis of mucositis was based on the nonspecific toxic effects of radiation or chemotherapy directed at the rapidly dividing cells of the oral basal epithelium. The paradigm directed that these cells were inhibited from proliferating, resulting in an atrophic oral mucosa which was easily damaged and failed to regenerate. While it is likely that the direct effect of radiation on epithelial cells plays a role in the generation of mucositis, current thinking suggests that the process is more biologically complex. It has been speculated that mucositis results from a process which includes changes in endothelium and connective tissue, as well as epithelium, that is stimulated by a number of cytokines [2]. The oral microbiotic flora, saliva and functional trauma provide an indigenous environment which modulates the frequency, course and severity of mucositis.

It seems likely that the initial oral tissue response to radiation occurs at the endothelial and connective tissue level. We have hypothesized that free radical formation leading to fibronectin disruption results in the activation of transcription factors, stimulation of pro-inflammatory cytokine production and tissue damage [3]. Earlier studies have shown a relationship between increased levels of pro-inflammatory cytokines in peripheral blood and the presence of non-hematologic toxicities [4]. Other data suggest that endothelial injury occurs simultaneously [5]. Concurrently, damage to the basal epithelial cells prevents their replication. No studies exist which have determined whether these cells undergo necrosis or apoptosis. Bacterial colonization of the damaged epithelium provides an opportunity for bacterial cell wall products to penetrate the injured mucosa and further stimulate the release of damaging cytokines.

Interleukin-11 (IL-11) is a pleiotropic 178-amino acid polypeptide with a molecular weight of 19 kDa which is expressed by a wide range of mesenchymal tissues [6]. Recombinant human IL-11 (rhIL-11) has a number of biologic activities which might impact on mucositis including modulation of inflammation, cellular proliferation and differentiation, protection of connective tissue and the inhibition of apoptosis induction [7], [8]. Subcutaneous administration of rhIL-11 reduces the frequency, severity, and duration of oral mucosal damage induced by 5-fluorouracil in hamsters [9]. In addition, IL-11 confers protection to the mucosa of the small intestine to challenges of either radiation or combined chemotherapy and radiation [10].

The objective of this investigation was to evaluate and define the mechanisms by which rh-IL-11 attenuates mucositis in response to acute radiation by evaluating its effect on mucosal levels of pro-inflammatory cytokine expression, apoptosis and morphologic changes.