Anti-proliferative effect of pro-inflammatory cytokines in cultured beta cells is associated with extracellular signal-regulated kinase 1/2 pathway inhibition: protective role of glucagon-like peptide -1.
Pancreatic beta-cell homeostasis is a balance between programmed cell death (apoptosis) and regeneration. Although autoimmune diabetes mellitus type 1 (DM1) is the most-studied cause of beta-cell mass loss by pro-inflammatory cytokine-induced apoptosis, influences of a pro-inflammatory environment on beta-cell regenerative response have been poorly studied. In this study, we assess the anti-proliferative effect of pro-inflammatory cytokines and glucose concentration on rat pancreatic beta cells and the potential protective role of glucagon-like peptide (GLP-1). Apoptotic and proliferating islet cells were stained using the DeadEnd Fluorimetric TUNEL System and 5-bromo-2'-deoxyuridine label respectively, in the presence-absence of varying concentrations of glucose, pro-inflammatory cytokines, and GLP-1. The potential signaling pathways involved were evaluated by western blot. Considerable anti-proliferative effects of pro-inflammatory cytokines interleukin (IL)-1beta, interferon (IFN)-gamma, and tumour necrosis factor-alpha (TNF-alpha) were observed. The effects were synergistic and independent of glucose concentration, and appeared to be mediated by the inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) activation, the signaling pathway involved in beta-cell replication. GLP-1 completely reversed the cytokine-induced inhibition of ERK phosphorylation and increased beta-cell proliferation threefold in cytokine-treated cultures. While pro-inflammatory cytokines reduced islet cell ERK1/2 activation and beta-cell proliferation in pancreatic islet culture, GLP-1 was capable of reversing this effect. These data suggest a possible pharmacological application of GLP-1 in the treatment of early stage DM1, to prevent the loss of pancreatic beta cells as well as to delay the development of overt diabetes.
Blandino-Rosano
M
M
Investigation Unit and Endocrinology and Nutrition Service, Puerta del Mar Hospital, Ana de Viya, 21, Cadiz 11009, Spain.
Perez-Arana
G
G
Mellado-Gil
J M
JM
Segundo
C
C
Aguilar-Diosdado
M
M
D000818:Animals; D018929:Cell Culture Techniques; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000502:physiology*; D052216:Glucagon-Like Peptide 1 / Q000502:physiology*; D005947:Glucose / Q000502:physiology; D018836:Inflammation Mediators / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000201:enzymology / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar
D016207:Cytokines; D018836:Inflammation Mediators; D052216:Glucagon-Like Peptide 1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D005947:Glucose