Cathelicidins positively regulate pancreatic beta-cell functions
2016 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 30, no 2, 884-894 p.Article in journal (Refereed) PublishedText
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.
Place, publisher, year, edition, pages
2016. Vol. 30, no 2, 884-894 p.
antimicrobial peptide, CRAMP, immunomodulation, endocrine cells, type 1 diabetes
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
IdentifiersURN: urn:nbn:se:uu:diva-281975DOI: 10.1096/fj.15-275826ISI: 000369391900036PubMedID: 26527065OAI: oai:DiVA.org:uu-281975DiVA: diva2:916205
FunderSwedish Research Council, 20854Swedish Research Council, 10350Swedish Research Council, K2014-67X-11217-20-3Swedish Foundation for Strategic Research , RBd08-0014
De två sista författarna delar sistaförfattarskapet.2016-04-012016-04-012016-04-01Bibliographically approved