Toll-like Receptors Regulate MIF Expression in Benign Lymphoepithelial Lesion of the Lacrimal Gland

Despite a perpetual increase in the prevalence of benign lymphoepithelial lesion, data on the mechanisms governing its pathogenesis are still missing. Thus, we aimed in the present study to evaluate whether TLRs could regulate the expression of the pleiotropic pro-inflammatory and tumor-related cytokine MIF in BLEL. Using gene expression profiling and protein expression analysis methods, we found that TLRs were overexpressed and that their signaling pathways were activated in BLEL. We have also confirmed in tissues biopsies, the overexpression of MIF reported previously in plasma of BLEL specimen. The analysis of the TLR7/8 impact on the expression of MIF in BLEL primary cells showed that when activated, TLR7/8 stimulate mainly BLEL lymphocytes to release MIF but not the fibroblast-like cells. No significant change was observed when MIF expression was investigated at the transcriptional level 24h post TLR7/8 activation. Taken together, these data suggest that TLR7 and TLR8 are activated in BLEL and may induce a cell type-dependent regulation of MIF secretion and expression

Macrophage migration inhibitory factor contributes to the pathogenesis of benign lymphoepithelial lesion of the lacrimal gland

Abstract Background Benign 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. Methods In 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. Results The 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. Conclusions Our 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

IgG4 and IgE co-positive group found in idiopathic orbital inflammatory disease

AIM: To reveal the cytokines involved in idiopathic orbital inflammatory disease (IOID) and the relationship between Th17 cells, IgE and IOID pathogenesis. METHODS: Whole blood samples were processed immediately after collection and serological IgG4, IgG, and IgE antibodies were tested using ELISA. IOID and orbital cavernous hemangioma (CH) tissue samples underwent Bio-Plex multiplex cytokine detection. Hematoxylin-Eosin (HE) staining of all paraffin samples suggested the histological features of IOIDs, and expressions of IgG4 and IL-17A in affected tissues were detected by immunohistochemistry. RESULTS: Among 40 IOID plasma samples, 52.5% (21/40) were positive for IgG4 and 25% (10/40) were positive for IgE. Overlapped IgG4 or IgE positive samples accounted for 22.5% (9/40). Therefore, IOID samples were separated into three groups. The IgE+/IgG4+ group had a relevantly lower level of pro-inflammatory cytokine expression. IL-4 (Th2 cell related), IL-10 and TGF-β1 (Treg cell immunity related) were elevated in all three groups. Some of the Th17 cell related cytokines (i.e. IL-17A/F, IL-25, IL-23, and IL-33) displayed higher expression levels in the IgE-/IgG4- group compared to the other two groups. CONCLUSION: We discovered an IgG4-IgE co-positive group as well as Th17 cell immune involvement in IgG4-IgE co-negative subgtroup in IOID for the first time. The pathogenesis of IOID could differ from different subgroups according to the IgG4 and IgE detection. Therefore, we recommend that, Treatment stratagy should be made according to the clinical assessment of IgG4-IgE and Th17 profile detection

Androgen deprivation induces double-null prostate cancer via aberrant nuclear export and ribosomal biogenesis through HGF and Wnt activation

Abstract Androgen deprivation therapy (ADT) targeting androgen/androgen receptor (AR)- signaling pathways is the main therapy for advanced prostate cancer (PCa). However, ADT eventually fails in most patients who consequently develop castration-resistant prostate cancer (CRPC). While more potent AR antagonists and blockers for androgen synthesis were developed to improve clinical outcomes, they also show to induce more diverse CRPC phenotypes. Specifically, the AR- and neuroendocrine-null PCa, DNPC, occurs in abiraterone and enzalutamide-treated patients. Here, we uncover that current ADT induces aberrant HGF/MET signaling activation that further elevates Wnt/β-catenin signaling in human DNPC samples. Co-activation of HGF/MET and Wnt/β-catenin axes in mouse prostates induces DNPC-like lesions. Single-cell RNA sequencing analyses identify increased expression and activity of XPO1 and ribosomal proteins in mouse DNPC-like cells. Elevated expression of XPO1 and ribosomal proteins is also identified in clinical DNPC specimens. Inhibition of XPO1 and ribosomal pathways represses DNPC growth in both in vivo and ex vivo conditions, evidencing future therapeutic targets