1. Introduction
Mucositis is the painful inflammation and ulceration of oral or
gastrointestinal tract and is usually caused by cancer
therapies.1 Thinning of the oral mucosa, a late side
effect of cancer treatment can cause chronic or non-healing ulcers.
Gastrointestinal obstruction, necrosis and perforation can also lead to
gastrointestinal damage.1,2 Side effects of cancer
treatment occur more in cells with rapid proliferation and normal
tissues containing rapidly growing cell populations of the host can also
be damaged.3 Chemotherapy and radiotherapy cause DNA
damage; they stimulate the formation of free oxygen radicals and can
directly affect non-DNA targets. As a result, macrophages are activated
and molecules that activate transcription factors, including nuclear
factor kappa B (NF-κB), are triggered. The production of proinflammatory
cytokines such as Tumor necrosis factor alpha (TNF-α), Interleukin
(IL)-6 and IL-1 increase. The mucosa becomes susceptible to bacterial
contamination because of tissue damage and ulceration. The mucosal
integrity in the epithelial cells is rearranged with the proliferation,
differentiation and migration and the recovery phase
begins.2,4 Mucositis may cause significant problems
such as abdominal pain, ulceration, dysphagia and diarrhea, decreased
fluid and nutrient intake, dehydration and weight loss. These problems
require parenteral nutrition of the patient and prolonged
hospitalization. Furthermore, they cause speech difficulties,
communication disorder, consequently, lowers the quality of life. The
prevalence of mucositis is three-fold higher in children than in adults
and can lead to serious respiratory disorders.5 The
development and recovery phase of mucositis vary according to the dose
and frequency of the drugs used and the tolerance of the
patient.2
Vitamin D (Vit D) is a crucial fat-soluble micronutrient that plays key
roles in bone and teeth development, protection from cardiovascular
diseases, cancer and regulation of immune system.6 Vit
D induces intestinal stem cell maturation and may suppress colitis by
protecting the mucosal epithelial barrier.7,8 Data
suggest that Vit D levels may impact mucositis severity. In pediatric
acute lymphoblastic leukemia patients above the age of 4, Vit D
deficiency has been reported. During methotrexate (MTX) therapy,
25(OH)D3 level was low and more severe oral mucositis was observed in
these patients.9 Importantly, a 59-year old patient
with breast carcinoma treated by docetaxel, trastuzumab and carboplatin
who had low Vit D levels initially, has been given Vit D and his
chemotherapy-dependent oral mucositis has improved.10Studies show that in Vit D receptor (VDR)-/- mice,
levels of IL-1β and TNF-α following induction of colitis were
elevated.11,12 Thus, these studies suggest that Vit D
may be beneficial may limit the severity of chemotherapy-induced
mucositis. However, to our knowledge, this has not yet been tested in an
animal model of mucositis.
IL-22, is a critical cytokine in modulating tissue responses during
inflammation. IL-22 is expressed by many lymphocytes, including T helper
(Th) 17, Th22, Natural killer T (NKT) cells, Group 3 Innate Lymphoid
Cells (ILC3s) and neutrophils.13 IL-22 binds to a
heterodimeric receptor composed of IL-22RA1 and IL-10RB subunits which
mainly expressed by non-hematopoietic cells, such as epithelial cells of
the gastrointestinal tract and skin.14 IL-22 is
constitutively expressed in the normal colon mucosa, and is critical in
barrier immunity, containment of microbiota on the luminal side of the
intestine, and intestinal tissue homeostasis.15 More
importantly, ILC3s cells have been shown to be play a protective role in
the murine methotrexate-induced mucositis model via IL-22 mediated
mechanisms.16 However, to our knowledge, whether
recombinant IL-22 or its over expression could be therapeutically
exploited to suppress or improve the severity of mucositis has not yet
been tested.
In this project, we aimed to test the therapeutic impact of Vit D
treatment or IL-22 overexpression on the methotrexate-induced mucositis
pathogenesis in Balb/c mice.