Interleukin-36 potently stimulates human M2 macrophages,Langerhans cells and keratinocytes to produce pro-inflammatory cytokines |
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| Institution: | 1. Department of Pathology and Immunology, University of Geneva, School of Medicine, Geneva, Switzerland;2. Division of Rheumatology, University Hospital Geneva, Switzerland;3. Unit of Immunopathology and Therapeutic Chemistry, Institute of Cellular and Molecular Biology, Strasbourg, France;4. Inflammation Research, Amgen Inc., South San Francisco, CA, USA;5. Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland;6. Division of Dermatology, University Hospital Geneva, Switzerland;1. Laboratory of Microbiology and Immunology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka City, Shizuoka 422-8526, Japan;2. Laboratory of Organic Chemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka City, Shizuoka 422-8526, Japan;1. Department of Immunology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15261, USA;2. Department of Biochemistry and Molecular Biology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou 215123, China;3. Department of Immunology, Institute of Medical Biotechnology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou 215123, China;4. University of Pittsburgh Cancer Institute, Pittsburgh, PA 15261, USA;5. Department of Tumor Biotherapy, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China;6. State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China;7. Department of Anesthesiology, University of Pittsburgh Medical Center, 3471 Fifth Avenue, Pittsburgh, PA 15213, USA;8. Department of Dermatology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15213, USA;9. Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006, China;10. School of Medicine, Tsinghua University, Peking 100084, China;11. Department of Pulmonary Tuberculosis, The Affiliated Hospital for Infectious Diseases of Soochow University, Suzhou 215007, China;12. Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China;13. Center for Inflammation, Immunity, and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA;14. Department of Surgery, The Second Hospital of Jilin University, Changchun 130041, China;15. Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA;16. Research and Development, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh PA 15240, USA;17. Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China;1. Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, China;2. Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm, Sweden;1. Faculty of Biological Sciences, School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, UK;2. Fraunhofer Institute for Toxicology and Experimental Medicine, Nikolai-Fuchs-Straße 1, 30625 Hannover, Germany;3. Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH) Research Network, Hannover, Germany;4. Department of Dermatology and Allergy, University of Bonn, Bonn 53012, Germany;5. Division of Infection, Immunity & Respiratory Medicine, University of Manchester, Manchester M13 9PL, UK;6. Division of Microbiology and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan;7. Faculty of Biology Medicine and Health, School of Biological Sciences, University of Manchester and Manchester Academic Health Science Centre, Manchester M13 9PL, UK;8. Faculty of Medicine and Health, Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds LS2 9JT, UK;9. Leeds Biomedical Research Centre, National Institute for Health Research, Leeds Teaching Hospitals, Leeds, UK;1. Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China;2. Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, Chongqing, China |
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| Abstract: | Interleukin (IL)-36 cytokines belong to the IL-1 family and include three agonists, IL-36 α, β and γ and one inhibitor, IL-36 receptor antagonist (IL-36Ra). IL-36 and IL-1 (α and β) activate similar intracellular pathways via their related heterodimeric receptors, IL-36R/IL-1RAcP and IL-1R1/IL-1RAcP, respectively. However, excessive IL-36 versus IL-1 signaling induces different phenotypes in humans, which may be related to differential expression of their respective receptors.We examined the expression of IL-36R, IL-1R1 and IL-1RAcP mRNA in human peripheral blood, tonsil and skin immune cells by RT-qPCR. Monocyte-derived dendritic cells (MDDC), M0, M1 or M2-polarized macrophages, primary keratinocytes, dermal macrophages and Langerhans cells (LC) were stimulated with IL-1β or IL-36β. Cytokine production was assessed by RT-qPCR and immunoassays.The highest levels of IL-36R mRNA were found in skin-derived keratinocytes, LC, dermal macrophages and dermal CD1a+ DC. In the blood and in tonsils, IL-36R mRNA was predominantly found in myeloid cells. By contrast, IL-1R1 mRNA was detected in almost all cell types with higher levels in tonsil and skin compared to peripheral blood immune cells. IL-36β was as potent as IL-1β in stimulating M2 macrophages, keratinocytes and LC, less potent than IL-1β in stimulating M0 macrophages and MDDC, and exerted no effects in M1 and dermal macrophages. Levels of IL-1Ra diminished the ability of M2 macrophages to respond to IL-1.Taken together, these data are consistent with the association of excessive IL-36 signaling with an inflammatory skin phenotype and identify human LC and M2 macrophages as new IL-36 target cells. |
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