Mycosis fungoides (MF) progresses from patch to tumor stage by expansion of malignant T-cells that fail to be controlled by protective immune mechanisms. In this study, we focused on IL-32, a cytokine, highly expressed in MF lesions. Depending on the other cytokines (IL-4, GM-CSF) present during in vitro culture of healthy volunteers' monocytes, IL-32 increased the maturation of CD11c+ myeloid dendritic cells (mDC) and/or CD163+ macrophages, but IL-32 alone showed a clear ability to promote dendritic cell (DC) differentiation from monocytes. DCs matured by IL-32 had the phenotype of skin-resident DCs (CD1c+), but more importantly, also had high expression of indoleamine 2,3-dioxygenase. The presence of DCs with these markers was demonstrated in MF skin lesions. At a molecular level, indoleamine 2,3-dioxygenase messenger RNA (mRNA) levels in MF lesions were higher than those in healthy volunteers, and there was a high correlation between indoleamine 2,3-dioxygenase and IL-32 expression. In contrast, Foxp3 mRNA levels decreased from patch to tumor stage. Increasing expression of IL-10 across MF lesions was highly correlated with IL-32 and indoleamine 2,3-dioxygenase, but not with Foxp3 expression. Thus, IL-32 could contribute to progressive immune dysregulation in MF by directly fostering development of immunosuppressive mDC or macrophages, possibly in association with IL-10.

Increasing evidence suggested the involvement of microRNA (miR)-146a in the pathogenesis of multiple diseases, including atherosclerosis, bacterial infection and cancer. However, the mechanism by which miR-146a is regulated in macrophages exposed to oxidized low-density lipoprotein (oxLDL) has remained elusive. The present study aimed to explore the molecular pathway of miR-146a regulation in response to oxLDL. Human THP-1 macrophages were pre-treated with small interfering RNA specific for scavenger receptors or with pharmacological inhibitors prior to oxLDL administration. A filter plate screening assay was performed to identify oxLDL-inducible transcription factors that bind to the miR-146a promoter. The exact binding sites were mapped by chromatin immunoprecipitation. The effects of miR-146a on markers of macrophage maturation were studied by flow cytometry. The results revealed that miR-146a expression was deceased when c-jun N-terminal kinase (JNK) or nuclear factor (NF)-κB signaling was inhibited. By forming a complex with c-jun, which was promoted by oxLDL, the NF-κB sub-unit p65 facilitated the binding of c-jun to the miR-146a promoter to trigger transcriptional activation. miR-146a negatively regulated macrophage maturation by reducing the expression of CD86 and CD80. The present study demonstrated that oxLDL positively regulates miR-146a via the JNK and NF-κB pathways in macrophages, and that miR-146a inhibits inflammatory activation.