Inhibition of fetal rat pancreatic β‐cell replication by interleukin‐1β in vitro is not mediated through pertussis toxin‐sensitive G‐proteins, a decrease in cyclic AMP, or protease activation

FEBS Letters

Sjöholm, Åke¹ 

[1] Department of Medical Cell Biology, Uppsala University, Box 571, S-751 23 Uppsala, Sweden

关键词: Cytokine;    Pancreatic islet;    DNA synthesis;    Insulin secretion;    Cyclic AMP;    Protease;   

DOI  :  10.1016/0014-5793(91)81081-I

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

It has been proposed that the cytokine interleukin-1β (IL-1β), secreted by islet-infiltrating macrophages, may be involved in the pathogenesis of insulin-dependent diabetes mellitus by participation in β-cell destruction. Addition of IL- 1β to isolated pancreatic islets in vitro results in cytotoxic effects on β-cell function, but there is little information on the intracellular events that convey the actions of the cytokine. In the present study, fetal rat pancreatic islets containing a high fraction of β-cells were exposed in culture to IL-1β. It was found that IL-1β markedly decreased β-cell DNA synthesis, insulin secretion and cyclic AMP content, In order to explore whether the decrease in cAMP resulted from IL-1β interaction with GTP-binding proteins coupled to adenylyl cyclase, islets were treated for 24h with pertussis toxin prior to addition of cytokine. While this treatment restored the decrease in cAMP, the reduced DNA synthesis and insulin secretion persisted. Pertussis toxin treatment without the addition of IL-1β resulted in increases in cAMP, DNA synthesis and insulin secretion. Addition of the stimulatory cAMP analog Sp-cAMPS also increased DNA synthesis and insulin secretion, but failed to affect the decrease in these functions evoked by IL-1β. The protease inhibitor Nα-p-tosyl-L-lysine chloromethyl ketone, recently shown to protect completely against IL-1β-induced suppression of insulin production and secretion, was found to markedly reduce DNA synthesis without affecting insulin secretion. When the protease inhibitor was combined with IL- 1β, the suppressed secretion was counteracted while DNA synthesis inhibition was not. It is concluded that cAMP stimulates DNA synthesis and insulin secretion in β-cells, but that the inhibitory effect of IL-1β on these functions cannot be ascribed to the decrease in cAMP evoked by the cytokine. However, the repressive effect of the cytakine on insulin secretion, but not DNA synthesis, may be prevented by protcase inhibition.

【 授权许可】

Unknown