期刊
FASEB JOURNAL
卷 30, 期 2, 页码 884-894出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.15-275826
关键词
antimicrobial peptide; CRAMP; immunomodulation; endocrine cells; type 1 diabetes
资金
- Rolf Luft Fellowship
- National Natural Science Foundation of China [31400779, 31570915]
- National Natural Science Foundation of China (National Youth 1000 Talents Plan)
- Provincial Natural Science Foundation of Jiangsu [BK20130133]
- Jiangsu Provincial Shuang Chuang Innovator Plan
- Icelandic Centre for Research
- Juvenile Diabetes Research Foundation-Helmsley [47-2013-524, 2-SRA-2015-73]
- European Foundation for the Study of Diabetes-Lilly
- Swedish Research Council [20854, 10350, K2014-67X-11217-20-3]
- Swedish Strategic Foundation [RBd08-0014]
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 beta cells and modulate beta-cell functions under steady-state or proinflammatory conditions are unknown. We find that cathelicidin-related antimicrobial peptide (CRAMP) is constitutively expressed by rat insulinoma b-cell clone INS-1 832/13. CRAMP expression is inducible by butyrate or phenylbutyric acid and its secretion triggered upon inflammatory challenges by IL-1 beta or LPS. CRAMP promotes b-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 beta-cell apoptosis, asmeasured 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 beta-cell functions and may be potentially used for intervening b-cell dysfunction-associated diseases.
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