Abstract
The Kallikrein–Kinin System (KKS), comprised of kallikreins (klks), bradykinins (BKs) angiotensin-converting enzyme (ACE), and many other molecules, regulates a number of physiological processes, including inflammation, coagulation, angiogenesis, and control of blood pressure. In this report, we show that KKS regulates Type I IFN responses, thought to be important in lupus pathogenesis. We used CpG (TLR9 ligand), R848 (TLR7 ligand), or recombinant IFN-α to induce interferon-stimulated genes (ISGs) and proteins, and observed that this response was markedly diminished by BKs, klk1 (tissue kallikrein), or captopril (an ACE inhibitor). BKs significantly decreased the ISGs induced by TLRs in vitro and in vivo (in normal and lupus-prone mice), and in human PBMCs, especially the induction of Irf7 gene (p < 0.05), the master regulator of Type I IFNs. ISGs induced by IFN-α were also suppressed by the KKS. MHC Class I upregulation, a classic response to Type I IFNs, was reduced by BKs in murine dendritic cells (DCs). BKs decreased phosphorylation of STAT2 molecules that mediate IFN signaling. Among the secreted pro-inflammatory cytokines/chemokines analyzed (IL-6, IL12p70, and CXCL10), the strongest suppressive effect was on CXCL10, a highly Type I IFN-dependent cytokine, upon CpG stimulation, both in normal and lupus-prone DCs. klks that break down into BKs, also suppressed CpG-induced ISGs in murine DCs. Captopril, a drug that inhibits ACE and increases BK, suppressed ISGs, both in mouse DCs and human PBMCs. The effects of BK were reversed with indomethacin (compound that inhibits production of PGE2), suggesting that BK suppression of IFN responses may be mediated via prostaglandins. These results highlight a novel regulatory mechanism in which members of the KKS control the Type I IFN response and suggest a role for modulators of IFNs in the pathogenesis of lupus and interferonopathies.
Highlights
The kallikrein–kinin system (KKS) is a metabolic cascade that releases vasoactive kinins upon triggering and has many pharmacological activities; KKS is involved in inflammation and cooperates with important pathways like the renin–angiotensin, coagulation, and complement [1,2,3]
We show that BKs and other molecules of the KKS system can suppress an ongoing Type I IFN response by decreasing the interferon-stimulated gene (ISG) expression, especially IRF7 the master regulator of Type I IFNs, both in mouse and human cells
Others, have shown that stimulation via TLR7 and TLR9 is important in the induction of Type I IFNs in lupus [14, 19, 23]
Summary
The kallikrein–kinin system (KKS) is a metabolic cascade that releases vasoactive kinins (bradykinin-related peptides) upon triggering and has many pharmacological activities; KKS is involved in inflammation and cooperates with important pathways like the renin–angiotensin, coagulation, and complement [1,2,3]. KKS Suppresses Type I IFN Responses plasma or tissue kallikreins (klks) [4] and acts via their receptors (B1 or B2) [5] to induce responses via nitric oxide and/or prostaglandin production [3]. There is increasing evidence that the KKS is involved in systemic lupus erythematosus (SLE) [10,11,12]. SLE is a systemic autoimmune disease of complex etiology in which immune complex deposition and complement activation lead to inflammation and tissue damage [13]. No link has so far been made between Type I IFNs and the KKS
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