Expression and function of leukaemia inhibitory factor and its receptor in normal and regenerating rat pancreas

Abstract

Aims/hypothesis: It was recently reported that culturing adult exocrine cells in the presence of epidermal growth factor and leukaemia inhibitory factor (LIF) resulted in their transdifferentiation into endocrine beta cells. The aim of this study was to examine the expression and function of LIF in the pancreas. Materials and methods: We studied the expression of LIF and its receptor components, LIF-receptor-β and gp130, by immunohistochemistry, western blotting and RT-PCR in normal rat pancreas, pancreas with duct ligation-induced islet neogenesis, and in pancreatic cell cultures. Isolated duct fragments were cultured in the presence of LIF and a janus kinase 2 (JAK2) inhibitor. Results: LIF was detected by immunohistochemistry, western blot and RT-PCR in the ducts of the normal pancreas. Both LIF-receptor-β and gp130 were detected by RT-PCR in the pancreas. Immunostaining revealed gp130 exclusively in the ducts and centro-acinar cells. After duct ligation-induced tissue injury, upregulation of LIF and its receptor occurred in rat pancreas. Metaplastic exocrine cells also started to express LIF and this was increased after alloxan treatment. Signalling via LIF-receptor-β/gp130 involves the JAK/signal transducer and activator of transcription (STAT) pathway. LIF induced increased activation of STAT3 in pancreatic cells. In isolated duct fragments, addition of LIF resulted in a significant increase in duct cell proliferation, while a specific inhibitor of the JAK/STAT signalling pathway inhibited proliferation. Conclusion/interpretation: Our observations show that LIF and its receptor are expressed in cells from pancreatic ducts. The cytokine plays a role in pancreatic physiology, controls duct cell proliferation and is involved in repair processes following pancreatic injury.

Expression of the Notch Signaling Pathway and Effect on Exocrine Cell Proliferation in Adult Rat Pancreas

“…We cannot exclude that during acinoductal metaplasia a parallel Notch/RBP-Jk-independent pathway is operating that results in the increased Hes1 expression. 40 This might also explain why L685,458 addition does not prevent acinoductal conversion in our culture conditions (unpublished observations). We found that ␥-secretase-inhibitors stimulated the proliferation of metaplastic exocrine cells and that this effect is coinciding with decreased Hey1 and Hey2 levels.…”

“…18,39 EGFR was reported before to act upstream of Notch in mouse exocrine cell culture. 18,40 Both EGFR and gp130 are expressed in pancreatic exocrine cells. 28,41 To uncover the function of Notch we used ␥-secretase inhibitors that are known to suppress Notch signaling.…”

Leukemia inhibitory factor as a regulator of steroidogenesis in human NCI-H295R adrenocortical cells

“…These phosphorylated tyrosine residues form docking sites for signaling molecules including the members of the signal transducer and activator of transcription (STAT) family (Ray et al 1996, Heinrich et al 2003. This signal transduction pathway has been confirmed, for instance, in rat pancreatic duct cells where the specific JAK2 phosphorylation inhibitor AG490 decreased basal and LIFinduced cell proliferation (De Breuck et al 2006).…”

“…IL1A, IL1B, TNF, and LPS (endotoxin) have been reported to upregulate LIF or LIFR mRNA in various tissues and cell types (Campbell et al 1993, Arici et al 1995, Grosset et al 1995, Wang et al 1996, De Breuck et al 2006, suggesting that a complex network of different cytokines may also function at the adrenal level. Further studies are needed to clarify the significance of the whole cytokine network in the regulation of human adrenal function in vivo, but it is tempting to speculate that LIF and TNF are factors modulating the activity of the hypothalamic-pituitary-adrenal axis, possibly at several levels in septic conditions and inflammatory states.…”

Origin of pancreatic endocrine cells from biliary duct epithelium

“…These also show no increase of cluster size relative to 2d controls, which would be expected if the primary effect were on division. We also studied EGF and the combination EGF+ LIF [28] on duct b-cells. Surprisingly their effects were negative.…”