Macrophage migration inhibitory factor as an incriminating agent in dermatological disorders.

Macrophage migration inhibitory factor (MIF) is a critical immunoregulatory pluripotent cytokine. It has been re-evaluated as a proinflammatory cytokine, pituitary hormone and glucocorticoid-induced immunoregulatory protein. MIF exists in human epidermis, especially in the basal layer and also is expressed constitutively by monocytes/macrophages, T cells, B cells, endocrine, and epithelial cells. In the field of dermatology, MIF is believed to be a detrimental factor in inflammatory dermatological diseases including atopic dermatitis (AD), psoriasis, vitiligo, pemphigus vulgaris, bullous pemphigoid (BP), alopecia areata (AA) as well as other conditions such as photoaging, and photocarcinigenesis. The objective of this review is to gather and summarize MIF related disorders in dermatology and present valuable information for readers and researchers.

What was known?

This is the first review regarding the role of MIF in dermatologic disorders.

Introduction

Cytokines possess pivotal role in the regulation of host responses to immune reactions, inflammation, infection, and trauma. Action of proinflammatory cytokines makes disease worse whereas anti-inflammatory cytokines serve to decrease inflammation and promote healing.[1] Macrophage migration inhibitory factor (MIF) was initially described almost 50 years ago as a cytokine that collects macrophages at inflammation sites and extensive studies have shown its critical role in innate and adaptive immunity.[23] It is composed of 114 amino acids and acts as a pleiotropic protein. This factor has tertiary structures[4] [Figure 1][5] and activates lymphocytes, granulocytes and monocytes/macrophages.[6] MIF acts as an isomerase, pituitary hormone and glucocorticoid-induced immunomodulator and MIF Messenger RNA (mRNA) is expressed in a variety of organs, including brain, kidney and liver.[4] Notably, this factor is expressed by a variety of cells such as eosinophils[7] lymphocytes[8] macrophages[9] epithelial[10] and endothelial cells,[11] therefore; MIF is thought to have a wide range of activities in skin disorders. The intention of this review was to concentrate and summarize MIF related articles in dermatology and introduce this molecule as a criminal agent.

Figure 1

Structure of the migration inhibitory factor protein (10)

Methodology

For this purpose, electronic databases including PubMed and ISI were searched to obtain studies giving any in vitro, in vivo, and human evidence following the methodology described by Liberatli et al.[12] The used limitations were (a) English language, (b) reference date field contains publication from 1990 to February 2012. The main key words used were “MIF”, “dermatology” and equivalent expressions and 49 references were included [Figure 2].

Figure 2

Example flow diagram of study selection

Results

Epidermal development and differentiation

The role of MIF mRNA in the development of epidermis and hair germ cells on rat was discovered by in situ hybridization.[13] Immunohistochemical researches have shown that MIF exists in human epidermis, mainly in the basal layer cells and it may play an important role in the differentiation of epidermal cells.[14]

Allergic and irritant contact dermatitis

MIF is thought to have a prominent role in the pathophysiology of experimental allergic inflammation. It can induce eosinophils accumulation in the skin and is critical to the generation of the antigen-specific immune response. Moreover, it is important in the initiation and maintenance of allergic diseases.[1516] It merits note that endothelial MIF expression is an essential agent in inflammatory type of macrophage and correlates with the severity of inflammation. A study demonstrated a strong endothelial MIF expression in the early phase of inflammation in both allergic and irritant contact dermatitis.[17] It has been postulated that MIF appears as the first molecular equivalent of developing inflammation[18] and it has a central role in Langerhans cell migration and T cell proliferation for contact hypersensitivity response.[19]

Atopic dermatitis

MIF is critical for mechanism of T-cell activation and delayed-type hypersensitivity in atopic dermatitis (AD). Reasonably, it has been implicated in the pathogenesis of AD and serum MIF content is elevated in patients with AD.[2021] In murine models of AD it has been documented that MIF-DNA vaccination not only prevents the progression of AD but also, improves the symptoms of pre-existing AD. It reduces histological finding of inflammation and serum Immunoglobulin E (IgE) in treated mice. Interestingly, using MIF-DNA vaccination and an anti-MIF autoantibody response may be a valuable approach in the treatment of AD.[22]

Psoriasis

Psoriasis is a chronic recurrent inflammatory skin condition[2324] which is believed to be a cell-mediated autoimmune disorder.[25] Researchers have suggested a role for MIF in the psoriasis disease.[26] Shimizu and colleagues demonstrated that in contrast to increased serum MIF levels in psoriasis patients, MIF-positive staining in the lesional psoriatic epidermis is decreased. It is hypothesized that MIF, a potential growth factor, maybe diminish in psoriatic lesions to counterregulate the abnormal epidermal proliferation caused by dysregulation of cytokines and growth factors. Notably, serum level of MIF and its production by peripheral blood mononuclear cells is closely correlated with the severity of clinical symptoms.[27] It has been reported that high MIF serum levels is associated with severe psoriasis.[28]

Vitiligo

Vitiligo is a frequent depigmenting disease with devastating psychosocial outcome.[29] The vitiligo pathogenesis is linked to cellular immunity. MIF is a powerful activator of macrophages and possesses a pivotal role in cell-mediated immunity. Serarslan and colleagues assessed the serum of 30 subjects with vitiligo. They demonstrated that mean serum MIF level is higher than that of controls, indicating the involvement of MIF in the pathogenesis of vitiligo.[30]

Alopecia areata

It has been recognized that serum MIF is elevated in patients with extensive alopecia areata (AA). Polymorphisms within the MIF-173*C allele confer an increased risk of susceptibility to the extensive forms of AA, especially with an early onset of disease. Considering that, MIF has been shown to be important in the pathogenesis of the more extensive forms of AA.[31]

Pemphigus vulgaris

Namazi et al. investigated the serum MIF levels using enzyme-linked immunosorbent assay (ELISA) technic in 22 patients with active pemphigus vulgaris and age- and sex-matched healthy controls. This study revealed the increased MIF in the sera of active pemphigus vulgaris patients could participate in disease induction by activation of T cells as well as stimulation of autoantibody synthesis by B cells. Additionally, MIF counter-regulates the impression of steroids and MIF antagonists may be very efficient as steroid-sparing drugs for this life-threatening disorder.[32]

Bullous pemphigoid

A study on the 21 patients with bullous pemphigoid (BP) and 45 healthy volunteers demonstrated that MIF levels in the serum and blister fluid of BP patients were increased. On the other hand, serum MIF levels were diminished in accordance with the amelioration of BP. Interestingly, MIF expression on the infiltrating cells was not detected.[33]

Photoaging

Matrix metalloproteinase (MMP)-1 degrades types I and III collagens. An in vivo animal study on the mice indicated that fibroblasts of IL-1alpha/beta-deficient produced low levels of MMPs subsequent to UVA radiation. Moreover, fibroblasts of MIF-deficient mice were much less sensitive to IL-1beta-induced MMPs synthesis. Accordingly, MIF could stimulate MMP-1 and participates in the loss of dermal collagen fiber in skin photoaging.[34]

Tumorigenes

Recent studies in mouse models have documented a role for MIF in the pathogenesis of non-melanoma skin cancer (NMSC) and progression in an inflammatory environment.[35] Importantly, chronic exposure to UVB increases MIF production, which may suppress the p53-dependent apoptosis and thereby induce skin tumor.[36] It merits note that tumor aggressiveness and metastatic potential in a variety of MIF's functions is unique among cytokines. Furthermore, its effects extend to several other actions including proliferation of the tumor, evasion of apoptosis, neovascularization and invasion.[37] Notably, immunohistochemical analysis has recognized that MIF is mainly localized in the melanocytes cytoplasm. Malignant melanoma is accompanied by over expression of MIF and it may act as a novel growth factor that induces growth and invasion of melanoma concomitant with angiogenesis [Table 1].[38]

Table 1

MIF-related dermatologic disorders

MIF is not always a bad omen

Wound healing

The role of MIF in accelerating wound healing is crucial and it responds to tissue injury and regulates immunological and inflammatory phases of wound process.[39] Immunohistochemical considerations have revealed the excessive expression of MIF in the wound tissue. This protein also exhibits a chemotactic effect on rat skin keratinocytes. Furthermore, cultured fibroblasts from the skin wound produce a higher amount of MIF in response to lipopolysaccharide and interestingly this factor is important in fibroblast migration and skin regeneration after wounding.[40] Also, MIF has been documented to be key effector of the beneficial effects of estrogen on wound healing.[41]

MIF as a valuable diagnostic test

Several studies have shown the diagnostic value of the MIF test in patients with the clinical diagnosis of drug eruption.[42] In an experimental study the diagnostic value of the MIF test was evaluated in 90 patients with drug eruption. The positive MIF responses in those in whom drugs were involved were higher than in those with eruptions in whom drugs were not involved. This test may be of aid in the diagnosis of drug eruptions and in the identification of the offending agent.[43]

Anti MIF drugs

Numerous groups of MIF inhibitors, including anti-MIF antibodies, small chemical compounds and plant-derived inhibitors have been recognized.[44] It has been identified that cetirizine influence MIF production.[45] Plant phenol anti-inflammatory compounds affect MIF tautomerase activity. Curcumin and caffeic acid are the most potent and resveratrol and umbelliferon are potent MIF inhibitors.[46]

Discussion

MIF has been the subject of intensive recent researches. It has proven to play a critical role for this molecule in innate and adaptive immunity. MIF is expressed by a variety of cells including eosinophils, lymphocytes, macrophages, epithelial cells as well as endothelial cells. This protein shifts macrophages to inflammation loci and also activates lymphocytes, granulocytes and monocytes/macrophages. In the field of dermatology, MIF is believed to be a criminal agent in many diseases but, its contribution to other aspects of skin biology is currently unknown.[47]

Considering that MIF has been manifested to be involved in the immunopathogenesis of cutaneous disorders; production of novel generations of the chemical or herbal preparations selective targeting of MIF, anti-MIF antibody and specific chemical MIF inhibitors can be the valuable therapeutic avenues in the future for the treatment of MIF-related dermatologic disorders. Moreover, according to the unique association between MIF and glucocorticoids, MIF antagonist agents can also highlight an impressive strategy for steroid-sparing therapies in patients with refractory autoimmune diseases.[48] Utilization of antibody, soluble receptor or small molecule technologies may result in the capacity to test in the clinic the value of MIF in inflammatory diseases.[49]

For the reason that MIF can potentially induce photocarcinogenesis, anti-MIF agents-containing sunscreens may be advantageous in Australasian countries and in cancer-prone disorders, such as xeroderma pigmentosum and Gorlin's syndrome. Finally, as MIF can stimulates MMP-1 and participates in the loss of interstitial collagen in skin aging, anti-MIF agent-containing creams may be of particular value in rejuvenation.

What is new?

Anti-MIF agents-containing sunscreens may be advantageous in cancer-prone disorders, such as xeroderma pigmentosum and Gorlin's syndrome.

Anti-MIF agent-containing creams may be of particular value in rejuvenation.