Thalidomide inhibits Toll-like receptor 7/9–mediated production of cytokines in murine splenic dendritic cells

Abstract

BACKGROUND: Dendritic cells (DCs), specialized sentinel cells that connect the innate and adaptive immune systems, play an important regulatory role in the inflammatory response by secreting cytokines and chemokines, which are linked to the development of various autoimmune diseases (ADs). Tolerogenic DCs can be induced by immunomodulators and have shown great promise for treating ADs. The immunomodulating drug thalidomide is a valuable AD treatment due to its inhibition of immune responses, likely through its effect on cytokines. This study investigated the mechanisms underlying thalidomide’s immunomodulatory activity on regulatory DCs. METHODS: Splenic CD11c+ DCs from C57BL/6J mice were obtained via magnetic-activated cell sorting (MACS™). Following stimulation with agonists of Toll-like receptors (TLRs) 7/9, quantitative real-time PCR and enzyme-linked immunosorbent assays were used to measure the mRNA and protein levels of three cytokines: interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-10. RESULTS: DCs stimulated with agonists of TLRs7/9 had significantly higher cytokine mRNA levels than the unstimulated control, which was reversed when the cells were cotreated with thalidomide. Treatment with agonists of TLRs7/9 stimulated significantly higher cytokine production from DCs than observed in the unstimulated control. This increased production was reduced when splenic DCs were cotreated with thalidomide. CONCLUSION: These findings suggest that thalidomide exerts its therapeutic effect on ADs by reducing the TLR7/9-mediated production of cytokines IL-6, TNF-α, and IL-10 in DCs. [Am J Transl Med 2021. 5 (2): 116-124].