Lactogens promote beta cell survival through JAK2/STAT5 activation and Bcl-XL upregulation.
One of the goals in the treatment for diabetes is to enhance pancreatic beta cell function, proliferation, and survival. This study explores the role of lactogenic hormones, prolactin (PRL) and placental lactogen (PL), in beta cell survival. We have previously shown that transgenic mice expressing mouse placental lactogen-1 (mPL1) in beta cells under the rat insulin II promoter (RIP) are resistant to the diabetogenic and cytotoxic effects of streptozotocin (STZ) in vivo. The current study demonstrates that lactogens protect rat insulinoma (INS-1) cells and primary mouse beta cells against two distinct beta cell death inducers, STZ and dexamethasone (DEX), in vitro. Further, we identify the mechanism through which lactogens protect beta cells against DEX-induced death. The signaling pathway mediating this protective effect is the janus-activated-kinase-2/signal transducer and activator of transcription-5 (JAK2/STAT5) pathway. This is demonstrated in INS-1 cells and primary mouse beta cells using three separate approaches, pharmacological inhibitors, JAK2-specific siRNAs and a dominant-negative STAT5 mutant. Furthermore, lactogens specifically and significantly increase the anti-apoptotic protein Bcl-XL in insulinoma cells and mouse islets. Bcl-XL-specific siRNA significantly inhibits lactogen-mediated protection against DEX-induced beta cell death. We believe this is the first direct demonstration of lactogens mediating their protective effect through the JAK2/STAT5 pathway in the beta cell and through Bcl-XL in any cell type.
Fujinaka
Yuichi
Y
Division of Endocrinology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Takane
Karen
K
Yamashita
Hiroko
H
Vasavada
Rupangi C
RC
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000633:toxicity; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D019610:Cytoprotection / Q000187:drug effects / Q000235:genetics; D003907:Dexamethasone / Q000633:toxicity; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D005799:Genes, Dominant; D007328:Insulin / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010928:Placental Lactogen / Q000235:genetics / Q000378:metabolism*; D011388:Prolactin / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism*
D000893:Anti-Inflammatory Agents; C494812:Bcl2l1 protein, mouse; C494813:Bcl2l1 protein, rat; D007328:Insulin; D034741:RNA, Small Interfering; D050799:STAT5 Transcription Factor; D051020:bcl-X Protein; D003907:Dexamethasone; D011388:Prolactin; D010928:Placental Lactogen; C507926:Jak2 protein, mouse; C507927:Jak2 protein, rat; D053614:Janus Kinase 2