title: Cathelicidins positively regulate pancreatic β-cell functions.
abstract: Cathelicidins are pleiotropic antimicrobial peptides largely described for innate antimicrobial defenses and, more recently, immunomodulation. They are shown to modulate a variety of immune or nonimmune host cell responses. However, how cathelicidins are expressed by β cells and modulate β-cell functions under steady-state or proinflammatory conditions are unknown. We find that cathelicidin-related antimicrobial peptide (CRAMP) is constitutively expressed by rat insulinoma β-cell clone INS-1 832/13. CRAMP expression is inducible by butyrate or phenylbutyric acid and its secretion triggered upon inflammatory challenges by IL-1β or LPS. CRAMP promotes β-cell survival in vitro via the epidermal growth factor receptor (EGFR) and by modulating expression of antiapoptotic Bcl-2 family proteins: p-Bad, Bcl-2, and Bcl-xL. Also via EGFR, CRAMP stimulates glucose-stimulated insulin secretion ex vivo by rat islets. A similar effect is observed in diabetes-prone nonobese diabetic (NOD) mice. Additional investigation under inflammatory conditions reveals that CRAMP modulates inflammatory responses and β-cell apoptosis, as measured by prostaglandin E2 production, cyclooxygenases (COXs), and caspase activation. Finally, CRAMP-deficient cnlp(-/-) mice exhibit defective insulin secretion, and administration of CRAMP to prediabetic NOD mice improves blood glucose clearance upon glucose challenge. Our finding suggests that cathelicidins positively regulate β-cell functions and may be potentially used for intervening β-cell dysfunction-associated diseases.
authors.affiliation: *State Key Laboratory of Food Science and Technology, School of Food Science and Technology and Synergetic Innovation Center of Food Safety and Nutrition, Jiangnan University, Wuxi, China; Biomedical Centre, Uppsala University, Uppsala, Sweden; Diabetes Research Unit, Department of Clinical Science and Education, Department of Physiology and Pharmacology, and The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden; Biomedical Center, University of Iceland, Reykjavik, Iceland; Institut National de la Santé et de la Recherche Médicale, Institute Necker-Enfants Malades, Centre National de la Recherche Scientifique, Paris, France; **Université Paris Descartes, Sorbonne Paris Cité, Paris, France; and Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden jiasun@jiangnan.edu.cn.
authors.forename: Jia
authors.initials: J
authors.lastname: Sun
authors.affiliation: *State Key Laboratory of Food Science and Technology, School of Food Science and Technology and Synergetic Innovation Center of Food Safety and Nutrition, Jiangnan University, Wuxi, China; Biomedical Centre, Uppsala University, Uppsala, Sweden; Diabetes Research Unit, Department of Clinical Science and Education, Department of Physiology and Pharmacology, and The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden; Biomedical Center, University of Iceland, Reykjavik, Iceland; Institut National de la Santé et de la Recherche Médicale, Institute Necker-Enfants Malades, Centre National de la Recherche Scientifique, Paris, France; **Université Paris Descartes, Sorbonne Paris Cité, Paris, France; and Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Meng
authors.initials: M
authors.lastname: Xu
authors.affiliation: *State Key Laboratory of Food Science and Technology, School of Food Science and Technology and Synergetic Innovation Center of Food Safety and Nutrition, Jiangnan University, Wuxi, China; Biomedical Centre, Uppsala University, Uppsala, Sweden; Diabetes Research Unit, Department of Clinical Science and Education, Department of Physiology and Pharmacology, and The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden; Biomedical Center, University of Iceland, Reykjavik, Iceland; Institut National de la Santé et de la Recherche Médicale, Institute Necker-Enfants Malades, Centre National de la Recherche Scientifique, Paris, France; **Université Paris Descartes, Sorbonne Paris Cité, Paris, France; and Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Ortsäter
authors.affiliation: *State Key Laboratory of Food Science and Technology, School of Food Science and Technology and Synergetic Innovation Center of Food Safety and Nutrition, Jiangnan University, Wuxi, China; Biomedical Centre, Uppsala University, Uppsala, Sweden; Diabetes Research Unit, Department of Clinical Science and Education, Department of Physiology and Pharmacology, and The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden; Biomedical Center, University of Iceland, Reykjavik, Iceland; Institut National de la Santé et de la Recherche Médicale, Institute Necker-Enfants Malades, Centre National de la Recherche Scientifique, Paris, France; **Université Paris Descartes, Sorbonne Paris Cité, Paris, France; and Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Lundeberg
authors.affiliation: *State Key Laboratory of Food Science and Technology, School of Food Science and Technology and Synergetic Innovation Center of Food Safety and Nutrition, Jiangnan University, Wuxi, China; Biomedical Centre, Uppsala University, Uppsala, Sweden; Diabetes Research Unit, Department of Clinical Science and Education, Department of Physiology and Pharmacology, and The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden; Biomedical Center, University of Iceland, Reykjavik, Iceland; Institut National de la Santé et de la Recherche Médicale, Institute Necker-Enfants Malades, Centre National de la Recherche Scientifique, Paris, France; **Université Paris Descartes, Sorbonne Paris Cité, Paris, France; and Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Lisa
authors.initials: L
authors.lastname: Juntti-Berggren
authors.affiliation: *State Key Laboratory of Food Science and Technology, School of Food Science and Technology and Synergetic Innovation Center of Food Safety and Nutrition, Jiangnan University, Wuxi, China; Biomedical Centre, Uppsala University, Uppsala, Sweden; Diabetes Research Unit, Department of Clinical Science and Education, Department of Physiology and Pharmacology, and The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden; Biomedical Center, University of Iceland, Reykjavik, Iceland; Institut National de la Santé et de la Recherche Médicale, Institute Necker-Enfants Malades, Centre National de la Recherche Scientifique, Paris, France; **Université Paris Descartes, Sorbonne Paris Cité, Paris, France; and Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Yong Q
authors.initials: YQ
authors.lastname: Chen
authors.affiliation: *State Key Laboratory of Food Science and Technology, School of Food Science and Technology and Synergetic Innovation Center of Food Safety and Nutrition, Jiangnan University, Wuxi, China; Biomedical Centre, Uppsala University, Uppsala, Sweden; Diabetes Research Unit, Department of Clinical Science and Education, Department of Physiology and Pharmacology, and The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden; Biomedical Center, University of Iceland, Reykjavik, Iceland; Institut National de la Santé et de la Recherche Médicale, Institute Necker-Enfants Malades, Centre National de la Recherche Scientifique, Paris, France; **Université Paris Descartes, Sorbonne Paris Cité, Paris, France; and Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Jesper Z
authors.initials: JZ
authors.lastname: Haeggström
authors.affiliation: *State Key Laboratory of Food Science and Technology, School of Food Science and Technology and Synergetic Innovation Center of Food Safety and Nutrition, Jiangnan University, Wuxi, China; Biomedical Centre, Uppsala University, Uppsala, Sweden; Diabetes Research Unit, Department of Clinical Science and Education, Department of Physiology and Pharmacology, and The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden; Biomedical Center, University of Iceland, Reykjavik, Iceland; Institut National de la Santé et de la Recherche Médicale, Institute Necker-Enfants Malades, Centre National de la Recherche Scientifique, Paris, France; **Université Paris Descartes, Sorbonne Paris Cité, Paris, France; and Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Gudmundur H
authors.initials: GH
authors.lastname: Gudmundsson
authors.affiliation: *State Key Laboratory of Food Science and Technology, School of Food Science and Technology and Synergetic Innovation Center of Food Safety and Nutrition, Jiangnan University, Wuxi, China; Biomedical Centre, Uppsala University, Uppsala, Sweden; Diabetes Research Unit, Department of Clinical Science and Education, Department of Physiology and Pharmacology, and The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden; Biomedical Center, University of Iceland, Reykjavik, Iceland; Institut National de la Santé et de la Recherche Médicale, Institute Necker-Enfants Malades, Centre National de la Recherche Scientifique, Paris, France; **Université Paris Descartes, Sorbonne Paris Cité, Paris, France; and Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Julien
authors.initials: J
authors.lastname: Diana
authors.affiliation: *State Key Laboratory of Food Science and Technology, School of Food Science and Technology and Synergetic Innovation Center of Food Safety and Nutrition, Jiangnan University, Wuxi, China; Biomedical Centre, Uppsala University, Uppsala, Sweden; Diabetes Research Unit, Department of Clinical Science and Education, Department of Physiology and Pharmacology, and The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden; Biomedical Center, University of Iceland, Reykjavik, Iceland; Institut National de la Santé et de la Recherche Médicale, Institute Necker-Enfants Malades, Centre National de la Recherche Scientifique, Paris, France; **Université Paris Descartes, Sorbonne Paris Cité, Paris, France; and Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Birgitta
authors.initials: B
authors.lastname: Agerberth
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D015232:Dinoprostone / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; C494820:Bad protein, mouse; C494821:Bad protein, rat; C494812:Bcl2l1 protein, mouse; C494813:Bcl2l1 protein, rat; C587672:IL1B protein, mouse; C000594089:IL1B protein, rat; D053583:Interleukin-1beta; D019253:Proto-Oncogene Proteins c-bcl-2; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; C052617:Bcl2 protein, mouse; C541485:EGFR protein, mouse; C483803:Egfr protein, rat; D066246:ErbB Receptors; D015232:Dinoprostone; D054804:Cathelicidins
keywords: CRAMP; antimicrobial peptide; endocrine cells; immunomodulation; type 1 diabetes