TLR2-Tpl2-dependent ERK Signaling Drives Opposite IL-12 Regulation in Dendritic Cells and Macrophages

Abstract

Abstract This study investigated responses to TLR2-driven ERK signaling in dendritic cells versus macrophages. TLR2 signaling was induced with Pam3Cys, and the role of ERK signaling was interrogated pharmacologically with a MEK1/2 inhibitor (U0126) or genetically using bone-marrow-derived macrophages or dendritic cells from Tpl2−/− mice. We assessed cytokine production via ELISA and mRNA levels by qRT-PCR. In macrophages, blockade of ERK signaling by pharmacologic or genetic approaches inhibited IL-10 production and increased IL-12p40 production significantly. In dendritic cells, blockade of ERK signaling similarly inhibited IL-10 production but decreased IL-12p40 production, opposite to the effect of ERK signaling blockade in macrophages. This difference in IL-12p40 regulation correlated with differential expression of transcription factors cFos and IRF1, which are known to regulate IL-12. Thus, the impact of ERK signaling in response to TLR2 stimulation differs between macrophages and dendritic cells, potentially regulating their distinctive functions in the immune system. ERK-mediated suppression of IL-12p40 in macrophages may prevent excess inflammation and associated tissue damage following TLR2-stimuation, while ERK-mediated induction of IL-12p40 in dendritic cells may promote priming of Th1 responses. Greater understanding of the role that ERK signaling plays in different immune cell types may inform the development of host-directed therapy for a number of infectious pathogens.