Kallikrein–Kinin System Suppresses Type I Interferon Responses: A Novel Pathway of Interferon Regulation
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 sho...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fimmu.2018.00156/full |
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| author | Alecia Seliga Michael Hweemoon Lee Nicole C. Fernandes Viviana Zuluaga-Ramirez Marta Didukh Yuri Persidsky Raghava Potula Stefania Gallucci Uma Sriram |
| author_facet | Alecia Seliga Michael Hweemoon Lee Nicole C. Fernandes Viviana Zuluaga-Ramirez Marta Didukh Yuri Persidsky Raghava Potula Stefania Gallucci Uma Sriram |
| author_sort | Alecia Seliga |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T13:16:07Z |
| format | Article |
| id | doaj.art-2a9b3e2f8a71490787fba578b9d1f6a1 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-11T13:16:07Z |
| publishDate | 2018-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-2a9b3e2f8a71490787fba578b9d1f6a12022-12-22T01:06:03ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-02-01910.3389/fimmu.2018.00156331025Kallikrein–Kinin System Suppresses Type I Interferon Responses: A Novel Pathway of Interferon RegulationAlecia Seliga0Michael Hweemoon Lee1Nicole C. Fernandes2Viviana Zuluaga-Ramirez3Marta Didukh4Yuri Persidsky5Raghava Potula6Stefania Gallucci7Uma Sriram8Department of Pathology and Laboratory Medicine, Temple University, Philadelphia, PA, United StatesLaboratory of Dendritic Cell Biology, Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United StatesDepartment of Pathology and Laboratory Medicine, Temple University, Philadelphia, PA, United StatesDepartment of Pathology and Laboratory Medicine, Temple University, Philadelphia, PA, United StatesDepartment of Pathology and Laboratory Medicine, Temple University, Philadelphia, PA, United StatesDepartment of Pathology and Laboratory Medicine, Temple University, Philadelphia, PA, United StatesDepartment of Pathology and Laboratory Medicine, Temple University, Philadelphia, PA, United StatesLaboratory of Dendritic Cell Biology, Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United StatesDepartment of Pathology and Laboratory Medicine, Temple University, Philadelphia, PA, United StatesThe 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.http://journal.frontiersin.org/article/10.3389/fimmu.2018.00156/fullkallikrein–kinin systembradykininsACE inhibitorsdendritic cellsPBMCTLR |
| spellingShingle | Alecia Seliga Michael Hweemoon Lee Nicole C. Fernandes Viviana Zuluaga-Ramirez Marta Didukh Yuri Persidsky Raghava Potula Stefania Gallucci Uma Sriram Kallikrein–Kinin System Suppresses Type I Interferon Responses: A Novel Pathway of Interferon Regulation Frontiers in Immunology kallikrein–kinin system bradykinins ACE inhibitors dendritic cells PBMC TLR |
| title | Kallikrein–Kinin System Suppresses Type I Interferon Responses: A Novel Pathway of Interferon Regulation |
| title_full | Kallikrein–Kinin System Suppresses Type I Interferon Responses: A Novel Pathway of Interferon Regulation |
| title_fullStr | Kallikrein–Kinin System Suppresses Type I Interferon Responses: A Novel Pathway of Interferon Regulation |
| title_full_unstemmed | Kallikrein–Kinin System Suppresses Type I Interferon Responses: A Novel Pathway of Interferon Regulation |
| title_short | Kallikrein–Kinin System Suppresses Type I Interferon Responses: A Novel Pathway of Interferon Regulation |
| title_sort | kallikrein kinin system suppresses type i interferon responses a novel pathway of interferon regulation |
| topic | kallikrein–kinin system bradykinins ACE inhibitors dendritic cells PBMC TLR |
| url | http://journal.frontiersin.org/article/10.3389/fimmu.2018.00156/full |
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