Leptin induces inflammation-related genes in RINm5F insulinoma cells.
BACKGROUND
Leptin acts not only on hypothalamic centers to control food intake but has additional functions in peripheral tissues, e.g. inhibition of insulin secretion from pancreatic islets. The leptin receptor (LEPRb) is a class I cytokine receptor that mediates activation of STAT transcription factors. In this study, we characterise the regulation of inflammation-related genes by leptin in insulinoma cells and compare the effect of transcriptional regulation by leptin with that of other cytokines.


RESULTS
We have used RINm5F insulinoma cells as a model system for a peripheral target cell of leptin. Six transcripts encoding inflammation-related proteins were found to be upregulated by activation of LEPRb, namely lipocalin-2, pancreatitis-associated protein, preprotachykinin-1, fibrinogen-beta, tissue-type plasminogen activator (tPA) and manganese-dependent superoxide dismutase (MnSOD). Four of these transcripts (fibrinogen-beta, lipocalin-2, tPA, MnSOD) were also induced by the proinflammatory cytokine interleukin-1beta (IL-1beta). Interferon-gamma alone had no effect on the leptin-induced transcripts but enhanced the upregulation by IL-1beta of lipocalin-2, tPA and MnSOD mRNA levels. Experiments with LEPRb point mutants revealed that the upregulation of the inflammation-related genes depended on the presence of tyrosine-1138 which mediates the activation of the transcription factors STAT1 and STAT3. Reporter gene assays showed that leptin induced the expression of preprotachykinin-1 and lipocalin-2 on the level of promoter regulation. Finally, leptin treatment increased caspase 3-like proteolytic activity in RINm5F cells.


CONCLUSIONS
The present data show that leptin induces a cytokine-like transcriptional response in RINm5F cells, consistent with the proposed function of leptin as a modulator of immune and inflammatory responses.
Hekerman
Paul
P
Institute of Pharmacology and Toxicology, Medical Faculty of the RWTH Aachen University, Aachen, Germany. paul.hekerman@web.de <paul.hekerman@web.de>
Zeidler
Julia
J
Korfmacher
Stefanie
S
Bamberg-Lemper
Simone
S
Knobelspies
Holger
H
Zabeau
Lennart
L
Tavernier
Jan
J
Becker
Walter
W
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D006224:Cricetinae; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D007249:Inflammation / Q000235:genetics*; D007340:Insulinoma / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D020738:Leptin / Q000378:metabolism*; D000071068:Lipocalin-2; D054834:Lipocalins; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D000073718:Pancreatitis-Associated Proteins; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D054411:Receptors, Leptin; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D015320:Tachykinins / Q000235:genetics / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D002352:Carrier Proteins; D053583:Interleukin-1beta; C097278:Lcn2 protein, rat; D020738:Leptin; D000071068:Lipocalin-2; D054834:Lipocalins; D000073718:Pancreatitis-Associated Proteins; D011498:Protein Precursors; C000612141:REG3A protein, human; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015320:Tachykinins; C044206:preprotachykinin; D014443:Tyrosine; D007371:Interferon-gamma; D020169:Caspases