The cytokine midkine (MK) is a growth factor that is involved in different physiological processes including tissue repair, inflammation, the development of different types of cancer and the proliferation of endothelial cells. The production of MK by primary human macrophages and monocyte-derived dendritic cells (MDDCs) was never described. We investigated whether MK is produced by primary human monocytes, macrophages and MDDCs and the capacity of macrophages and MDDCs to modulate the proliferation of endothelial cells through MK production. The TLR stimulation of human monocytes, macrophages and MDDCs induced an average of ≈200-fold increase in MK mRNA and the production of an average of 78.2, 62, 179 pg/ml MK by monocytes, macrophages and MDDCs respectively (p < 0.05). MK production was supported by its detection in CD11c+ cells, CLEC4C+ cells and CD68+ cells in biopsies of human tonsils showing reactive lymphoid follicular hyperplasia. JSH-23, which selectively inhibits NF-κB activity, decreased the TLR-induced production of MK in PMBCs, macrophages and MDDCs compared to the control (p < 0.05). The inhibition of MK production by macrophages and MDDCs using anti-MK siRNA decreased the capacity of their supernatants to stimulate the proliferation of endothelial cells (p = 0.01 and 0.04 respectively). This is the first study demonstrating that the cytokine MK is produced by primary human macrophages and MDDCs upon TLR triggering, and that these cells can stimulate endothelial cell proliferation through MK production. Our results also suggest that NF-κB plays a potential role in the production of MK in macrophages and MDDCs upon TLR stimulation. The production of MK by macrophages and MDDCs and the fact that these cells can enhance the proliferation of endothelial cells by producing MK are novel immunological phenomena that have potentially important therapeutic implications.
This study would enhance pathologists' ability to diagnose and differentiate between different types of epithelial lesions reliably.Methods: This study is a retrospective observational cross-sectional study. A total of 117 immuno histoche mical tests for p16 were collected from the pathology lab at SQUH from January 2010 to December 2020. Data was analyzed using SPSS software. For numerical data, mean and percentages were used. For measuring the association between different pathological and clinical findings, the categorized variables were analyzed using the chi-square test.Results: Immunohistochemistry of p16 was mainly used to diagnose uterine cervical, ovarian, oropharyngeal and anal epithelial lesions. Predominately, it was applied on cervical intraepithelial neoplasia grades 1, 2 and 3 (CIN I, II, III), squamous metaplasia, chronic cervicitis, anal intraepithelial neoplasia as well as different types of squamous cell carcinoma, adenocarcinoma, and serous carcinoma. Conclusions:The results of the present study revealed the wide application of p16 IHC as a marker to reach the final histopathological diagnosis of epithelial lesions in the pathology lab at SQUH. The marker can be used effectively to differentiate between different types of lesions showing similar appearance on hematoxylin and eosin stain.
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