MMP-9 Inhibits IL-23p19 Expression in Dendritic Cells By Targeting Membrane Stem Cell Factor Affecting Lung IL-17 Response

摘要

We previously reported that c-kit ligation by membrane-bound stem cell factor (mSCF) boosts IL-6 production in DCs and a Th17 immune response. However, Th17 establishment also requires heterodimeric IL-23 but the mechanisms that regulate IL-23 gene expression in DCs are not fully understood. Here we show that IL-23p19 gene expression in lung DCs is dependent on mSCF, which is regulated by the metalloproteinase MMP-9. Th1-inducing conditions enhanced MMP-9 activity causing cleavage of mSCF whereas the opposite was true for Th17-promoting conditions. In MMP-9^−/− mice, a Th1-inducing condition could maintain mSCF and enhance IL-23p19 in DCs promoting IL-17-producing CD4+ T cells in the lung. Conversely, mSCF cleavage from bone marrow DCs in vitro by recombinant MMP-9 led to reduced IL-23p19 expression under Th17-inducing conditions with dampening of intracellular AKT phosphorylation. Collectively, these results show that the c-kit/mSCF/MMP-9 axis regulates IL-23 gene expression in DCs to control IL-17 production in the lung.