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Diabetologia
Published in: Diabetologia 7/2004

01-07-2004 | Article

Cytokines activate genes of the endocytotic pathway in insulin-producing RINm5F cells

Authors: K. L. A. Souza, M. Elsner, P. C. F. Mathias, S. Lenzen, M. Tiedge

Published in: Diabetologia | Issue 7/2004

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Abstract

Aims/hypothesis

Cytokines are important humoral mediators of beta cell destruction in autoimmune diabetes. The aim of this study was to identify novel cytokine-induced genes in insulin-producing RINm5F cells, which may contribute to beta cell death or survival.

Methods

A global gene expression profile in cytokine-exposed insulin-producing RINm5F cells was achieved by automated restriction fragment differential display PCR. The expression of selected candidate genes was confirmed by real-time RT-PCR analysis.

Results

Exposure of RINm5F cells to IL-1β or to a cytokine mixture (IL-1β, TNF-α, IFN-γ) for 6 h resulted in the differential expression of a functional gene cluster. Apart from the well-known up-regulation of the cytokine-responsive genes iNOS, NF-κB, MnSOD and Hsp70, several genes that belong to the functional cluster of the endocytotic pathway were identified. These endocytotic genes comprised: clathrin, megalin, synaptotagmin and calcineurin, which were up-regulated by IL-1β or the cytokine mixture. In contrast, the expression of the calcineurin inhibitor CAIN and of the GDP/GTP exchange protein Rab3 was down-regulated by cytokines. Other up-regulated cytokine-responsive genes were: agrin, murine adherent macrophage protein mRNA (MAMA) and transport-associated protein (TAP1/MTP), whereas the plasma membrane calcium ATPase (PMCA) 2 and PMCA 3 genes were down-regulated by cytokines.

Conclusions/interpretation

Our results indicate that genes of the endocytotic pathway are regulated by pro-inflammatory cytokines. This might affect the density of cytokine receptors at the beta cell surface and concomitantly the sensitivity of the cells to cytokine toxicity. A better understanding of the functional cross-talk between endocytotic and cytokine signalling pathways could further the development of novel strategies to protect pancreatic beta cells against toxic effects of pro-inflammatory cytokines.
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Metadata
Title
Cytokines activate genes of the endocytotic pathway in insulin-producing RINm5F cells
Authors
K. L. A. Souza
M. Elsner
P. C. F. Mathias
S. Lenzen
M. Tiedge
Publication date
01-07-2004
Publisher
Springer Berlin Heidelberg
Published in
Diabetologia / Issue 7/2004
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-004-1435-2

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