Metalloproteinase activity inhibits IL-23p19 expression in dendritic cells by targeting membrane stem cell factor affecting lung IL-17 response. (IRC5P.458)
2014
Ligation of c-kit by membrane-bound stem cell factor (mSCF) leads to DC IL-6 production and a Th17 immune response, which also requires heterodimeric IL-23. However, the mechanisms regulating IL-23 production in DCs are not fully understood. We found that IL-23p19 gene expression in lung DCs is dependent on mSCF, which itself is regulated by metalloproteinase activity. Th1-inducing conditions enhanced protease activity causing cleavage of mSCF whereas the opposite was true for Th17-promoting conditions. In metalloproteinase-deficient mice, Th1-inducing conditions maintained mSCF expression thereby enhancing IL-23p19 in DCs. The functional consequence of this was enhanced IL-17 production in T cell/DC co-cultures in vitro, and increased numbers of IL-17-producing CD4+ T cells in the lung. Conversely, mSCF cleavage from bone marrow DCs in vitro by recombinant metalloproteinase led to reduced IL-23p19 expression under Th17-inducing conditions with dampening of intracellular AKT phosphorylation, a key component of the c-kit signaling pathway. Collectively, these results show that IL-23 production in DCs can be regulated by metalloproteinase activity on the c-kit/mSCF axis to control IL-17 production in the lung.
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