Abstract
BackgroundStudies into the regulation of interleukin-10 (IL-10), have focused only on the molecular or single-cell level. The cues that induce IL-10 in the context of cell-to-cell communication are scarce. To fill this gap, this study elucidates the cell-to-cell interaction dependent regulation of IL-10.ResultsThe simultaneous activation of CD4+ T cells via CD3/CD28 and stimulation of macrophages via CpG and their intercellular communication with each other in the same microenvironment is necessary to induce a synergistic expression of IL-10. NF-κB1, ERK, and STAT3 are positive regulators of this cell-to-cell communication mediated molecular change of IL-10 induction. Strikingly, the activation of CD40/CD154 signaling is a negative regulator of IL-10 levels by CD3/CD28/CpG.ConclusionsThese findings are of prominence as CD3/CD28/CpG treatment can induce the anti-inflammatory cytokines IL-10 and IL-30, and the activation or inhibition of the CD40/CD154 acts as molecular rheostat of the expression of IL-10 or IL-30. More importantly, this not only serves as an example of IL-10 regulation at the cellular via coordination of two signals from two cell types, but these findings also lay the molecular and cellular groundwork for future studies to investigate how to manipulate IL-10 or IL-30 production during inflammation, cancer, or autoimmune diseases.
Highlights
Studies into the regulation of interleukin-10 (IL-10), have focused only on the molecular or single-cell level
While many studies have attempted to understand the regulation of IL-10 in a specific cell type through a specific stimulus, the role of cell-to-cell communication or interaction in the induction of IL-10 is largely unknown
The rationale for using splenocytes was that this cell mixture represents a variety of immune cells, and additive or synergistic effects of different stimuli can be observed. These two sets of signals, CD3/CD28 plus CpG (CD3/CD28/CpG), synergistically induces high levels of the anti-inflammatory cytokine IL-30 [16], suggesting that the same phenomenon may occur in IL-10 regulation
Summary
Studies into the regulation of interleukin-10 (IL-10), have focused only on the molecular or single-cell level. IL-10 has been shown to be a feedback regulator of Th1, Th2, and allergenic immune responses [3,4] This cytokine is produced by different immune cell types, including B cells, macrophages, mast cells, neutrophils, dendritic cells (DC), and several T cell subsets (including Th1, Th17, Foxp3+ Tregs, and regulatory type 1 cells Tr1) [5,6,7,8]. Different cues within the microenvironment regulate the IL-10 expression in a cell-specific manner. This observation is of importance as IL-10 expression by different cells, namely effector CD4+ or regulatory T (Treg) cells, can have different roles in the same infection. In Th1 cells, MAF and SMAD4 are key IL-10 transcription factors; in Th2 cells, GATA3, Jun, and MAF are specific transcription factors for IL-10 expression, while STAT3 or STAT1 are the important factors for IL10 in Th17 expression [11,12,13,14]
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