Interleukin-1 regulates keratinocyte expression of T cell targeting chemokines through interleukin-1 receptor associated kinase-1 (IRAK1) dependent and independent pathways |
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| Authors: | Julio C Sanmiguel Florina Olaru Jieliang Li Elisabeth Mohr Liselotte E Jensen |
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| Institution: | 1. National Institute for Public Health and the Environment, Center for Health Protection, Bilthoven 3721 MA, The Netherlands;2. Leiden University Medical Center, Department of Toxicogenetics, Leiden 2300 RC, The Netherlands;3. Dutch Molecular Pathology Center, Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht 3584 CL, The Netherlands;1. Department of Immunology, Institut Curie, Paris, France;4. Research Section, Institut Curie, Paris, France;9. Department of Surgery, Institut Curie, Paris, France;2. Laboratory of Neuroimmunology, Fondazione Santa Lucia, Rome, Italy;3. Institut National de la Santé et de la Recherche Médicale U932, Paris, France;5. Department of Dermatology, Heinrich Heine University, Düsseldorf, Germany;6. Department of Microbiology, Infectiology and Immunology, CHU Sainte-Justine and University of Montreal, Montreal, Quebec, Canada;7. CHU Sainte-Justine Research Center, Montreal, Quebec, Canada;8. Départment de Chirurgie, Hopital Pitié Salpétrière, Paris, France;10. Laboratory of Molecular and Cellular Neurobiology, Fondazione Santa Lucia, Rome, Italy;11. Department of Dermatology, University of Rome Tor Vergata, Rome, Italy;12. Laboratory for Investigative Dermatology, Rockefeller University, New York, NY;13. Laboratory of Experimental Immunology, IDI-IRCCS, Rome, Italy;1. Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, Switzerland;2. Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia;3. Institute of Molecular and Cellular Biology, University of Tartu, Tartu, Estonia;4. Transgenic Technology Core Laboratory, University of Tartu, Tartu, Estonia;5. Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary;6. Dermatological Research Group of the Hungarian Academy of Sciences, Szeged, Hungary;7. Department of Pathology, Tartu University Hospital, Tartu, Estonia;8. Department of Dermatology and Venereology, University of Tartu, Tartu, Estonia;9. Dermatology Clinic, Tartu University Hospital, Tartu, Estonia;10. Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale/Université de Strasbourg, Illkirch, France;11. Department of Molecular and Cellular Biology, Beckman Research Institute, City of Hope, Duarte, Calif;1. Laboratory of Cell Signaling and Nanomedicine, Department of Dermatology, Division of Brain Korea 21 Project for Biomedical Science, Korea University College of Medicine, Seoul, Republic of Korea;2. Research Institute for Skin Image, Korea University College of Medicine, Seoul, Republic of Korea;3. Departments of Dermatology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan |
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| Abstract: | IL-1 is a potent pro-inflammatory cytokine that activates intracellular signaling cascades some of which may involve IL-1 receptor associated kinase-1 (IRAK1). Psoriasis is a T cell dependent chronic inflammatory condition of the skin of unknown cause. IL-1 has been implicated in psoriasis pathology, but the mechanism has not been elucidated. Interestingly, expression of IRAK1 is elevated in psoriatic skin. To identify a potential link between IL-1, keratinocytes and T cells in skin inflammation we employed pathway-focused microarrays to evaluate IL-1 dependent gene expression in keratinocytes. Several candidate mRNAs encoding known T cell chemoattractants were identified in primary keratinocytes and the stable keratinocyte cell line HaCaT. CCL5 and CCL20 mRNA and protein levels were confirmed up-regulated by IL-1 in concentration and time-dependent manners. Furthermore IL-1 synergized with IFN-γ and TNF-α. Expression of CXCL9, CXCL10 and CXCL11 mRNAs was also increased in response to IL-1, but protein could only be detected in medium from cells treated with IFN-γ alone or in combination with IL-1. Over-expression of IRAK1 led to increased constitutive and cytokine induced production of CCL5 and CCL20. Inhibition of IRAK1 activity through RNAi or expression of a dominant negative mutant blocked production of CCL5 and CCL20 but had no effect upon the IL-1 enhancement of IFN-γ induced CXCL9, CXCL10 and CXCL11 production. In conclusion IL-1 regulates T cell targeting chemokine production in keratinocytes through IRAK1 dependent and independent pathways. These pathways may contribute to acute and chronic skin inflammation. |
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