Endogenously produced TNF-alpha contributes to the expression of CXCL10/IP-10 in IFN-lambda 3-activated plasmacytoid dendritic cells

摘要

The interplay between IFN-lambda s and dendritic cells is becoming increasingly relevant, particularly in light of their key role in inducing the antiviral state, including in hepatitis C virus infection. In this work, we have analyzed extensively how human plasmacytoid dendritic cells respond to IFN-lambda 3. We report that plasmacytoid dendritic cells incubated with IFN-lambda 3 prolong their survival; alter their expression pattern of surface HLA-DR alpha, CD123, CD86, and CD303; and time dependently produce IFN-alpha, CXCL10/IFN-gamma-induced protein 10, and even modest quantities of TNF-alpha. Nevertheless, endogenously produced TNF-alpha, but not IFN-alpha, was found to be essential for driving the expression of CXCL10/IFN-gamma-induced protein 10 in IFN-lambda 3-treated plasmacytoid dendritic cells, as revealed by neutralizing experiments by use of adalimumab, etanercept, and infliximab. We also observed that based on the kinetics and levels of IFN-a and CXCL10/IFN-gamma-induced protein 10 produced by their IFN-lambda 3-treated plasmacytoid dendritic cells, healthy donors could be categorized into 2 and 3 groups, respectively. In particular, we identified a group of donors whose plasmacytoid dendritic cells produced modest quantities of CXCL10/IFN-gamma-induced protein 10; another one whose plasmacytoid dendritic cells produced elevated CXCL10/IFN-gamma-induced protein 10 levels, already after 18 h, declining thereafter; and a 3rd group characterized by plasmacytoid dendritic cells releasing very high CXCL10/IFN-g-induced protein 10 levels after 42 h only. Finally, we report that in plasmacytoid dendritic cells, equivalent concentrations of IFN-lambda 3 and IFN-lambda 1 promote survival, antigen modulation, and cytokine production in a comparable manner and without acting additively/synergistically. Altogether, data not only extend the knowledge on the biologic effects that IFN-ls exert on plasmacytoid dendritic cells but also add novel light to the networking between IFN-lambda s and plasmacytoid dendritic cells in fighting viral diseases.