Kallikrein-Kinin System suppresses Type I Interferon (IFN) responses: a novel mechanism of IFN regulation.

Abstract

Abstract Kallikrein-Kinin System (KKS) that comprises of kallikreins (klks), bradykinins (bk), angiotensin converting enzyme (ACE), and many other molecules, have classically known to be involved in a variety of physiological processes, including coagulation, angiogenesis and control of blood pressure. The role of KKS in regulating immune responses has come to light recently. Recent reports indicate that KKS is involved in lupus and giving exogenous klks can ameliorate lupus in mice. We have reported earlier the expression of a Type I IFN signature by dendritic cells (DCs) from the B6.Sle1, 2, 3 congenic model of lupus-prone mice. In this study, we directly asked the question if exogenous KKS regulates IFN induced responses. We used Flt3L induced bone-marrow-derived DCs from normal C57BL/6 (B6) mice and PBMC from normal human donors for in vitro studies. We stimulated the cells with recombinant IFN-α, IFN-β, CpG (TLR9 ligand), or R848 (TLR7 ligand) to induce IFN responses, and further treated with KKS candidates [Lys-bk, Hyp-bk, klk]. We analyzed the IFN induced responses by Interferon Stimulated Gene (ISG) expression and cytokine production. KKS candidates suppressed IFN or TLR induced IRF7 gene expression and CXCL10 production in both mouse DCs and human PBMCs. KKS candidates also suppressed IFN or TLR induced IL-6. We also used HOE140, a bk receptor 2 antagonist, and observed that blocking bk signaling increased the IFN responses in vitro. In vivo administration of Hyp-bk after IFN induction with CpG strongly decreased IRF7 and CXCL10 gene expression in B6 splenocytes, confirming our in vitro observations. Our results suggest a novel pathway of Type I IFN regulation by the KKS and opens up a new direction for designing drug targets for lupus.