title: Galectin-3 deficiency protects pancreatic islet cells from cytokine-triggered apoptosis in vitro.
abstract: Beta cell apoptosis is a hallmark of diabetes. Since we have previously shown that galectin-3 deficient (LGALS3(-/-) ) mice are relatively resistant to diabetes induction, the aim of this study was to examine whether beta cell apoptosis depends on the presence of galectin-3 and to delineate the underlying mechanism. Deficiency of galectin-3, either hereditary or induced through application of chemical inhibitors, β-lactose or TD139, supported survival and function of islet beta cells compromised by TNF-α + IFN-γ + IL-1β stimulus. Similarly, inhibition of galectin-3 by β-lactose or TD139 reduced cytokine-triggered apoptosis of beta cells, leading to conclusion that endogenous galectin-3 propagates beta apoptosis in the presence of an inflammatory milieu. Exploring apoptosis-related molecules expression in primary islet cells before and after treatment with cytokines we found that galectin-3 ablation affected the expression of major components of mitochondrial apoptotic pathway, such as BAX, caspase-9, Apaf, SMAC, caspase-3, and AIF. In contrast, anti-apoptotic molecules Bcl-2 and Bcl-XL were up-regulated in LGALS3(-/-) islet cells when compared to wild-type (WT) counterparts (C57BL/6), resulting in increased ratio of anti-apoptotic versus pro-apoptotic molecules. However, Fas-triggered apoptotic pathway as well as extracellular signal-regulated kinase 1/2 (ERK1/2) was not influenced by LGALS-3 deletion. All together, these results point to an important role of endogenous galectin-3 in beta cell apoptosis in the inflammatory milieu that occurs during diabetes pathogenesis and implicates impairment of mitochondrial apoptotic pathway as a key event in protection from beta cell apoptosis in the absence of galectin-3.
authors.affiliation: Department of Immunology, Institute for Biological Research Siniša Stanković, University of Belgrade, Belgrade, Serbia.
authors.forename: Tamara
authors.initials: T
authors.lastname: Saksida
authors.forename: Ivana
authors.initials: I
authors.lastname: Nikolic
authors.forename: Milica
authors.initials: M
authors.lastname: Vujicic
authors.forename: Ulf J
authors.initials: UJ
authors.lastname: Nilsson
authors.forename: Hakon
authors.initials: H
authors.lastname: Leffler
authors.forename: Miodrag L
authors.initials: ML
authors.lastname: Lukic
authors.forename: Ivana
authors.initials: I
authors.lastname: Stojanovic
authors.forename: Stanislava
authors.initials: S
authors.lastname: Stosic-Grujicic
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002470:Cell Survival; D016207:Cytokines / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D037502:Galectin 3 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D018836:Inflammation Mediators / Q000502:physiology; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000502:physiology*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000502:physiology; D019014:fas Receptor / Q000502:physiology
chemical_list: D016207:Cytokines; C491899:Fas protein, mouse; D037502:Galectin 3; D018836:Inflammation Mediators; C485095:Lgals3 protein, mouse; D019014:fas Receptor