Role of interleukin-4 in pathogenesis of oral lichen planus: A systematic review

Background Oral lichen planus (OLP) is a premalignant mucocutaneous disease that affects 1-2% of the adult population. Immunological factor may act as etiological factor. The cellular immune cells such as T cells are important in pathogenesis of OLP. Interleukin-4 (IL-4) is secreted by T-helper 2 (Th2). Several studies have been carried out on the role of IL-4 in OLP. The aim of this study was to review the level of IL-4 in OLP, effective factors in the production of IL-4 and its role in the development of OLP. Material and Methods A search in PubMed was performed on the literature published from 2000 until august 2019 using the following keywords: “oral lichen planus” or “OLP” and “interleukin-4” or “IL-4”. Results Originally, 37 articles were considered, of which 28 case-control articles were selected according to the inclusion/exclusion criteria. Conclusions This review study shows that IL-4 plays a key role in the development of OLP. According to the past studies, there are several factors contributing to the production of this cytokine. Identification of the routes of production of IL-4 and its role in OLP might be useful for development of new preventive and therapeutic methods in management of patients with OLP. Key words:Interleukin 4, oral lichen planus, pathogenesis.


Introduction
Oral lichen planus (OLP) is recognized as a chronic inflammatory disease with other systemic disorders. Its prevalence ranges from 1% to 2% among the general population. It often involves middle-aged patients and is more common in women than in men (1,2). Although the etiology of OLP is unknown, various mechanisms have been suggested to be involved in its pathogenesis (specific immune response to antigens, immune response, humoral immunity, and nonspecific mechanisms). OLP is a T-cell-induced autoimmune disorder in which CD8 + cells can induce apoptosis in oral epithelial cells. T States MEDLINE was used as search source. The keywords were selected based on Medical Subject Heading (MeSH) terms. The studies were retrieved by searching the key terms "oral lichen planus" or "OLP" and "interleukin-4" or "IL-4" in PubMed databases from 2000 up to august 2019.
-Study selection and selection criteria A protocol was used for establishment of the inclusion and exclusion criteria. The studies on the association between OLP and IL-4 were selected without restrictions of variants of OLP. To select the studies, all obtained English language reports were reviewed, and titles and abstracts were screened for relevance. Studies were excluded if they were review or animal studies. Duplicate publications (risk of bias), were removed from the study.
-Data extraction The studies were checked by one author (P.M.) to extract all the relevant data. Another author (M.A) reevaluated the data. Disagreements were resolved with the third author's discussion (S.P.M).

-Study selection
In an initial research, 37 articles were identified through electronic database. The full texts of these studies were assessed for eligibility and 9 studies were excluded with reasons (5 studies were review/systematic review, 1 reported the polymorphisms of other cytokine, 1 was performed on animals, 1 was performed on cutaneous lichen planus and 1 study was published in Chinese) that shown in Fig. 1.
helper cells (Th) are traditionally divided into two subgroups (Th1 and Th2). Accordingly, impaired immune regulation has been implicated in the cause of OLP. Cytokines can play a mediating role between keratinocytes and inflammatory cells, and they also play important roles in damaging keratinocytes (3)(4)(5)(6). Interleukin-4 (IL-4) is an important cytokine that is responsible for the secretion of other cytokines. It plays a central role in regulating antibody production and humoral immune response to differentiate Th2 cells (7)(8)(9)(10). Several studies have been carried out on the role of IL-4 in OLP. Some studies have examined IL-4 levels in the tissues; saliva and serum in OLP, and contradictory results have been presented. Other studies have examined the factors affecting the production of IL-4 and the mechanisms of lesions of OLP formation by this cytokine. Our purpose in this study has been placed on the levels of IL-4 in different samples, production of IL-4 and its role in the development of OLP in this review. Identification of the routes of production of IL-4 and its role in OLP might be useful for development of new preventive and therapeutic methods in management of patients with OLP as well.

Author
Year Sample Results Wei (12) 2018 Saliva No significant difference in salivary IL-4 between OLP and control groups.
HU JY (13) 2015 serum The IL-4 level decreased in erosive OLP group, and was much lower than that of nonerosive OLP group. It also revealed that the expression of miR-155 in peripheral blood might be associated with the levels of IL-4.
Malekzadeh (14) 2015 Saliva The salivary IL-4 level in case group was significantly increased compared with control group Wang (15) 2015 serum & tissue IL-4 levels increased in the serum and lesional tissue compared with those of the controls.

Saliva & Serum
OLP patient showed a high-level IL-4 expression profile in both serum and saliva. Serum IL-4 level in the erythematous/ulcerative group was significantly higher than that in the reticular group.
Piccini (17) 2014 tissue mRNA expression for IL-4 was significantly higher in erosive OLP compared with their tissue controls. No significant difference was observed in produced IL-4 by CD4+ T-cell clones derived from erosive and reticular lesions.

Serum & PBMC
A higher level of IL-4 in PBMC and serum specimen of OLP patients was observed. A negative correlation between Golli-MBP (a regulator of autogenic T cells) and IFN-γ / IL-4 gene expression was observed in PBMCs but not in serum levels of OLP patients.
HU JY (19) 2013 Serum The levels of serum IL-4 in OLP patients were apparently lower than that in controls. Th1-type cytokines environment presented in OLP probably performed as a magnifier for the CCR5.
Pekiner (20) 2012 Serum There were no statistically significant differences in relation to the IL-4 levels between the investigated groups Zhou (21) 2012 Serum IL-4 levels were significantly lower in OLP patients than in controls. The low serum IL-4 in OLP confirms that mainly PD-1/B7-H1 pathway is implicated in OLP from another side.
Liu (22) 2009 Saliva OLP patient showed a high-level IL-4 expression profile in saliva, With regards to subtypes, salivary IL-4 level in erythematous/ulcerative group was significantly higher than that in reticular group.

Saliva & tissue
In OLP lesions, IL-4 in erythematous ⁄ ulcerated OLP was higher significantly than that in control specimens. In saliva, no significant difference was observed

Results of studies
Effecting factor in IL-4 production in patient with OLP

Year Authour
Following TRIM21 overexpression, no significant changes in IL-4 levels were observed.

TRIM21 2019
Wei (26) Exogenous IGF1, rapamycin and LY294002 alone had no effects on the production of IL-4. However, when IGF1 co-stimulated with rapamycin or LY294002, the secretion of IL-4 was restricted in comparison with controls. Kalogerakou (37) 2008 no statistical difference was observed in the number of IL-4 producing cells between OLP patients and controls Bai (38) 2008 There was no difference between the OLP patient and healthy control groups in frequencies of both the IL-4 allele and genotype, although the frequencies of the IL4-590 C allele and the CC genotype.
PPD: purified protein derivative

Discussion
Although the exact cause of OLP is still unknown, it has been widely accepted that immunodeficiency cases are very important. The role of Th1 / Th2 imbalance in the pathogenesis of OLP has been widely studied among several etiologic agents in the Past years (4,7,8). Given the expression of Th1 cytokines by T cells in OLP lesion lymphocytes and the pathological hypothesis of OLP that Th1-activated auto cytotoxic CD8 T cells induce apoptosis of keratinocytes, Sugerman et al.
suggested that OLP was characterized by Th1 cytokines (10). However, concomitant expression of Th1 and Th2 cytokines is observed in localized OLP lesions and tissue secretions. In addition, saliva, serum, and peripheral blood mononuclear cells from OLP patients have a complex expression profile of Th1 and Th2 cytokines.
There is no doubt that both Th1 and Th2 immune responses are involved in the development of OLP. Interferon gamma (IFN-γ) and IL-4, the most characteristic of Th1 and Th2 cytokines, regulate T cell differentiation and Th1 / Th2 balance, respectively, in physiological and pathological immune processes. IFN-γ is involved in the maturation and activation of cytotoxic CD8 T cells and maintenance of the expression of major class II tissue adhesion molecules, thus participating in keratinocyte apoptosis and chronic OLP. IL-4 disease, on the other hand, for Th2 cell differentiation and it has an important role in regulating antibody production and humoral immune response (4,7,8). Table 1 presents contradictory results on the levels of IL-4 in different samples. This disagreement may be due in part to patient differences, subgroups of OLP, research methods, or sample size, but also suggests that mechanisms such as the role of T regulatory cells and new Th cell subsets may exist, in the etiology of OLP except for the Th1 / Th2 imbalance. Another important factor to consider is the interaction of genes and cytokines as well as the effect of gene polymorphisms on cytokine production. Indeed, a study of Chinese ethnicity showed that IL-4 gene polymorphism had a positive effect on OLP sensitivity and prognosis (38). It may therefore explain the differences between results in numerous studies. In addition, according to the studies in the present review, none of them examined the effect of age and sex on IL-4 levels, although we believe that these factors should be taken into account in future studies. The most important point to be drawn from these tables is that the levels of interleukin but not its secretory cells are higher in most studies in the Lichen Planus group than in healthy individuals, thus indicating that IL-4 may represent a potential salivary biomarker for the disease. Taking advantage of easy access and noninvasive collection by intermediate-educated individuals, whole saliva offers a cost-effective way to monitor recurrent diseases and screen large populations in studies of Systemic diseases, especially oral diseases, which is consistent with a recent systematic review (40).
In most of these studies, interleukin-4 levels are higher in the erosive form than in the reticular type, which may be attributed to more inflammation and infection in the erosive form, or to the possible role of interleukin in the conversion of the reticular to the erosive type through impaired keratinocyte repair. Another point to note is that the levels of interleukin-4 in HCV-ve are not different from those of HCV+ve, so this cytokine is not an important factor in the development of lichen planus in hepatitis c-positive individuals (24). Also, the level of this cytokine in patients with SCC is lower than in those with lichen planus. It can be concluded that interleukin is not an important factor in the development of malignancy in lichen planus (35