Abstract
BackgroundBenign Lymphoepithelial Lesion (BLEL) is a rare disease observed in the adult population. Despite the growing numbers of people suffering from BLEL, the etiology and mechanisms underlying its pathogenesis remain unknown.MethodsIn the present study, we used gene and cytokines expression profiling, western blot and immunohistochemistry to get further insight into the cellular and molecular mechanisms involved in the pathogenesis of BLEL of the lacrimal gland.ResultsThe results showed that Macrophage Migration Inhibitory Factor (MIF) was the most highly expressed cytokine in BLEL, and its expression positively correlated with the expression of Th2 and Th17 cells cytokines. MIF was found to regulate biological functions and pathways involved in BLEL pathogenesis, such as proliferation, resistance to apoptosis, MAPK and PI3K/Akt pathways. We also found that MIF promotes fibrosis in BLEL by inducing BLEL fibroblast differentiation into myofibroblasts as well as the synthesis and the deposit of extracellular matrix in BLEL tissues.ConclusionsOur findings demonstrate the contribution of MIF to the pathogenesis of BLEL of the lacrimal gland and suggested MIF as a promising therapeutic target for its treatment.
Highlights
Benign Lymphoepithelial Lesion (BLEL) is a rare disease observed in the adult population
migration inhibitory factor (MIF) promotes cell proliferation and migration by interacting with its proposed receptors cluster of differentiation 74 (CD74), C-X-C chemokine receptor 2 (CXCR2), CXCR4, and CXCR7 [13, 16,17,18,19], which may trigger the activation of several pathways, including mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Akt pathways, facilitating the activation of transcription factors required for the expression of pro-inflammatory cytokines and cell cycle regulators, for cell migration, proliferation, and survival [13, 16,17,18,19]
MIF regulates biological functions and pathways involved in BLEL pathogenesis To directly link MIF to the pathologic features observed in BLEL, we evaluated its effects on cell proliferation, apoptosis, and the MAPK and PI3K/Akt cascades, given that they were shown to play a role in BLEL pathogenesis by our upstream analysis
Summary
Benign Lymphoepithelial Lesion (BLEL) is a rare disease observed in the adult population. Benign lymphoepithelial lesion (BLEL), referred to as Mikulicz disease, is characterized by the bilateral swelling of salivary and lacrimal glands and immunoglobulin G4 (IgG4)-positive plasma cell infiltration in the affected tissues [1, 2]. Macrophage migration inhibitory factor (MIF) is a pleiotropic, pro-inflammatory cytokine that has been implicated in the pathogenesis of several inflammatory disorders, autoimmune diseases, and tumors [13,14,15]. MIF has both pro-fibrotic [23, 26,27,28] and anti-fibrotic [22, 29] activities, the precise mechanisms of these functions in fibrosis remain unclear
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