Immune-mediated β-cell destruction in vitro and in vivo—A pivotal role for galectin-3

doi:10.1016/j.bbrc.2006.03.105

Biochemical and Biophysical Research Communications

Volume 344, Issue 1, 26 May 2006, Pages 406-415

https://doi.org/10.1016/j.bbrc.2006.03.105 Get rights and content

Abstract

Pro-apoptotic cytokines are toxic to the pancreatic β-cells and have been associated with the pathogenesis of Type 1 diabetes (T1D). Proteome analysis of IL-1β exposed isolated rat islets identified galectin-3 (gal-3) as the most up-regulated protein. Here analysis of human and rat islets and insulinoma cells confirmed IL-1β regulated gal-3 expression of several gal-3 isoforms and a complex in vivo expression profile during diabetes development in rats. Over-expression of gal-3 protected β-cells against IL-1β toxicity, with a complete blockage of JNK phosphorylation, essential for IL-1-mediated apoptosis. Mutation scanning of regulatory and coding regions of the gal-3 gene (LGALS3) identified six polymorphisms. A haplotype comprising three cSNPs showed significantly increased transmission to unaffected offspring in 257 T1D families and replicated in an independent set of 170 T1D families. In summary, combined proteome–transcriptome–genome and functional analyses identify gal-3 as a candidate gene/protein in T1D susceptibility that may prove valuable in future intervention/prevention strategies.

Section snippets

Materials and methods

Islet isolation and cell culture. Neonatal islets from pancreata of 4- to 5-day-old BB-DP/Wor/Mol-BB and BB-DR/Wor/Mol-WB rats (M & B, Ll. Skensved, Denmark) were isolated [14], [29].

Human islets were isolated from cadaver organ donors at the University of Miami, FL [30]. RIN cells (RIN-5AH-T2B) were cultured as previously described [31]. The cytokines added to the islets and RIN cells were recombinant human IL-1β (Novo Nordisk, Bagsværd, Denmark) and recombinant mouse IL-1β (BD Pharmingen, San

Effect of cytokines on gal-3 expression in islets of Langerhans and β-cells

Our previous proteome analysis of Wistar–Furth (WF) rat islets, detecting approximately 1,500 different protein-spots [9], revealed a gal-3 containing spot to be the most up-regulated (24-fold) following IL-1β exposure based on % IOD [10], [13] (Table 1). Subsequent analyses of IL-1β exposed islets from the BioBreeding diabetes prone (BB-DP) rat strain revealed a significant smaller IL-1β induced upregulation (2.1-fold; p < 0.01) of gal-3 expression (spot x in Fig. 1 and Table 1) [14], however

Discussion

Cytokines have been proposed as effector molecules in the destruction of pancreatic β-cells and to be important in the initiation of autoimmune diabetes [1], [46]. By proteome-based characterization of the mechanisms involved in β-cell destruction [9], [10], [11], [12], [13], [14] we identified gal-3 as the most up-regulated protein in WF-rat islets following cytokine exposure [13]. Subsequent analysis of islets transplanted to BB-DP rats further demonstrated a complex regulation of gal-3

Acknowledgments

We thank B.B. Jørgensen, S. Munch, E. Schjerning, J.K. Skalshoei, and C. Christensen for excellent technical assistance, and doctors and nurses participating in the collection of families for genetic studies. We are grateful to all the patients and their families that contributed to this study. The isolated islets were prepared by the University of Miami Diabetes Research Institute Islet Cell Resource (ICR) center. This work was supported by grants from the European Commission (BMH4-CT97-2311),

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Galectin-3 in T cell-mediated immunopathology and autoimmunity
2021, Immunology Letters
Citation Excerpt :
IL-1β regulated Gal-3 expression during diabetes development in rats. Overexpression of Gal-3 protects β-cells against IL-1β toxicity with a complete blockage of JNK phosphorylation [80]. Interestingly, in our ongoing work, in type 1 diabetes, we observed that genetic overexpression of Gal-3 in the islets may attenuate oxidative stress in β-cells (to be reported).
Galectin-3 (Gal-3) is the only member of galectin family able to form pentamers and heterodimers with chemokines. Its presence in various cells and tissues suggests variety of regulatory functions in physiological conditions, but increasing body of evidence indicates involvement of Gal-3 in pathological cascades of many diseases. Gal-3 exerts different, sometimes opposite, effects in various disorders or in different phases of the same disease. These differences in action of Gal-3 are related to the localization of Gal-3 in the cell, types of receptors through which it acts, or the types of cells that secrete it. As a regulator of immune response and T-cell activity, Gal-3 appears to have important role in development of autoimmunity mediated by T cells. Absence of Gal-3 in C57Bl6 mice favors Th2 mediated inflammatory myocarditis but attenuate fibrosis. Recent data also indicate Gal-3 involvement in development atherosclerosis. In pathogenesis of diabetes type 1 and autoimmune components of diabetes type 2 Gal-3 may have detrimental or protective role depending on its intracellular or extracellular localization. Gal-3 mediates autoimmune hepatic damage through activation of T-cells or natural killer T cells. Gal-3 is an important mediator in neurodevelopment, neuropathology and behavior due to its expression both in neurons and glial cells. All together, assessing the role of Gal-3 in immunopathology and autoimmunity it could be concluded that it is an important participant in pathogenesis, as well as promising monitoring marker and therapeutic target.
Assessment of serum galectin-3, methylated arginine and Hs-CRP levels in type 2 diabetes and prediabetes
2019, Life Sciences
Citation Excerpt :
Insulin levels in galectin-3 knockout mice have been found higher in the healthy group compared to the diabetic group [11]. It has been shown the overexpression of galectin-3 prevented the beta cell destroyed because of the effect of pro-apoptotic cytokines [12]. Furthermore, strong evidence for galectin-3 have been shown that it is involved in the pathogenesis of diabetic complications via receptor function for advanced glycation end products (AGEs) and developing lipoxidation end products (ALEs) [5].
Galectin-3 is associated with the process of inflammation and fibrosis. The aim of this study was both to evaluate of galectin-3, methylated arginines and hs-CRP in subjects with type 2 diabetes and prediabetes and to investigate a relation between serum galectin-3, methylated arginines and hs-CRP levels.
In this study, all subjects were defined as the control group, type 2 diabetes (n = 84) by fasting plasma glucose and prediabetes (n = 34) by 75-g oral glucose tolerance test. Also, participants with type 2 diabetes were divided into as group I (HbA1c ≤7%, n = 40) and group II (HbA1c ≥7%, n = 44). The analysis of serum methylated arginines levels was analyzed by tandem mass spectrometry. Galectin-3 levels were determined via chemiluminescent microparticle immunoassay (CMIA).
Serum galectin-3, ADMA, L-NMMA and SDMA levels were significantly lower in the control group (13.3 ± 3.42; 0.630 (0.13–1.36); 0.176 (0.02–0.53); 0.115 (0.04–0.26), respectively) compared to diabetic subjects (15.71 ± 4.22; 0.825 (0.23–2.80); 0.366 (0.08–1.41); 0.1645 (0.06–0.47), p = 0.002, p = 0.01, p = 0.001 and p = 0.006, respectively). Galectin-3 was positively correlated with hs-CRP (r = 0.295 p = 0.001), L-NMMA (r = 0.181 p = 0.022), HbA1c (r = 0.247 p = 0.002), neopterin (r = 0.160 p = 0.045) and FPG (r = 0.207 p = 0.001) respectively. Also, there was positively correlated ADMA with FPG (r = 0.192 p = 0.016) and eAG (r = 0.235 p = 0.003).
Thus, galectin-3 might be a useful prognostic marker in the population with prediabetes and diabetes. Moreover, it can be a marker showing the condition of developing complications in diabetic patients.
Untangling Galectin-Driven Regulatory Circuits in Autoimmune Inflammation
2018, Trends in Molecular Medicine
Citation Excerpt :
Furthermore, preventive long-term treatment with recombinant Gal9 given once per week until 50 weeks of age delayed the onset of the disease in NOD mice (Figure 1) [48]. Finally, Gal3 is extensively expressed by both rat and human isolated islets in response to IL-1β in vitro and in vivo during spontaneous development of T1D in the Bio-Breeding diabetes-prone rat strain [49]. Interestingly, Lgals3−/− mice develop attenuated diabetes in response to multiple low-doses of streptozotocin, as demonstrated by reduced glycemia and lower insulitis [50].
Although progress has been made in understanding the mechanisms implicated in the pathogenesis of autoimmune inflammation, studies aimed at identifying the mediators of these pathways will be necessary to develop more selective therapies. Galectins, a family of glycan-binding proteins, play central roles in immune cell homeostasis. Whereas some members of this family trigger regulatory programs that promote resolution of inflammation, others contribute to perpetuate autoimmune processes. We discuss the roles of endogenous galectins and their specific glycosylated ligands in shaping autoimmune responses by fueling, extinguishing, or rewiring immune circuits. Understanding the relevance of galectin–glycan interactions in autoimmune inflammation could help to uncover novel pathways of tolerance breakdown, define molecular signatures for patient stratification and therapy responses, and open new avenues for immune intervention.
Krüppel-like factor 3 (KLF3/BKLF) is required for widespread repression of the inflammatory modulator galectin-3 (Lgals3)
2016, Journal of Biological Chemistry
Citation Excerpt :
It is notable that these metabolic complications do not develop in Klf3−/− mice even when they are maintained on a high-fat diet (23). Additionally, we observed significant galectin-3 up-regulation in the pancreas of Klf3−/− mice, where galectin-3 has been shown to protect β cells from the inflammatory effects of interleukin 1β (8). We also found that Lgals3 expression is elevated in Klf3−/− heart tissue, which may be important in the context of current research efforts focused on galectin-3 in cardiac function (5, 39).
The Lgals3 gene encodes a multifunctional β-galactoside-binding protein, galectin-3. Galectin-3 has been implicated in a broad range of biological processes from chemotaxis and inflammation to fibrosis and apoptosis. The role of galectin-3 as a modulator of inflammation has been studied intensively, and recent evidence suggests that it may serve as a protective factor in obesity and other metabolic disorders. Despite considerable interest in galectin-3, little is known about its physiological regulation at the transcriptional level. Here, using knockout mice, chromatin immunoprecipitations, and cellular and molecular analyses, we show that the zinc finger transcription factor Krüppel-like factor 3 (KLF3) directly represses galectin-3 transcription. We find that galectin-3 is broadly up-regulated in KLF3-deficient mouse tissues, that KLF3 occupies regulatory regions of the Lgals3 gene, and that KLF3 directly binds its cognate elements (CACCC boxes) in the galectin-3 promoter and represses its activation in cellular assays. We also provide mechanistic insights into the regulation of Lgals3, demonstrating that C-terminal binding protein (CtBP) is required to drive optimal KLF3-mediated silencing. These findings help to enhance our understanding of how expression of the inflammatory modulator galectin-3 is controlled, opening up avenues for potential therapeutic interventions in the future.
The pancreatic β cell and type 1 diabetes: Innocent bystander or active participant?
2013, Trends in Endocrinology and Metabolism
Citation Excerpt :
Combined proteome–transcriptome–genome approaches identified galectin-3 as a candidate gene/protein in T1DM susceptibility. Galectin-3 expression is induced by IL-1β exposure in rat and human islets, with overexpression of galectin-3 protecting β cells against IL-1β, in part through a blockade of JNK phosphorylation [70]. Studies within a T1DM-associated linkage region on chromosome 21 have also identified several genes with altered expression following cytokine exposure [71], including carbonyl transferase (CBR1), which functions as a nitrosylated glutathione reductase important for β cell survival during oxidative stress [72], and the E3 ligase protein tetratricopeptide repeat domain 3 (TTC3), which facilitates the ubiquitination and degradation of the survival factor Akt/PKB [73].
Type 1 diabetes mellitus (T1DM) is a chronic disease resulting from destruction of insulin-producing pancreatic β cells. Genetic and environmental factors contribute to T1DM onset. Use of high-throughput DNA sequencing has allowed geneticists to perform genome-wide association studies (GWAS) to identify novel gene loci associated with T1DM. Interestingly, >50% of these genes encode products that are expressed in β cells. These studies, coupled with emerging molecular evidence that β cells are impaired by gain-of-function or loss-of-function of these loci, suggest an active role for the β cell in eliciting its own demise. Although immune dysregulation plays a vital role in T1DM pathogenesis, understanding the mechanisms contributing to β cell failure may lead to new strategies to preserve or improve β cell function in patients with T1DM.
Galectin-3 Impairs Calcium Transients and β-Cell Function
2024, Research Square

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¹: Shared first authorship.

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Immune-mediated β-cell destruction in vitro and in vivo—A pivotal role for galectin-3

Abstract

Section snippets

Materials and methods

Effect of cytokines on gal-3 expression in islets of Langerhans and β-cells

Discussion

Acknowledgments

Mol. Cell. Proteomics

Trends Immunol.

Biochim. Biophys. Acta

FEBS Lett.

Exp. Neurol.

J. Biol. Chem.

J. Biol. Chem.

Am. J. Hum. Genet.

Biochem. Pharmacol.

J. Biol. Chem.

Arch. Biochem. Biophys.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

On the pathogenesis of IDDM

Diabetologia

The role of interleukin-1 in the pathogenesis of insulin-dependent diabetes mellitus

Diabetologia

An update on cytokines in the pathogenesis of insulin-dependent diabetes mellitus

Diabetes/Metab. Rev.

Combined genome and proteome approach to identify new susceptibility genes

Am. J. Med. Genet.

Proteome analysis—a novel approach to understand the pathogenesis of type 1 diabetes mellitus

Disease Markers

Use of microarray analysis to unveil transcription factor and gene networks contributing to β cell dysfunction and apoptosis

Ann. N.Y. Acad. Sci

Two-dimensional gel electrophoresis of rat islets proteins: Interleukin-1 beta induced changes in protein expression are reduced by l-arginine depletion and nicotinamide

Diabetes

Interleukin-1beta induced changes in the protein expression of rat islets

Electrophoresis

Islet protein expression changes during diabetes development in islet syngrafts in BB-DP rats and during rejection of BB-DP islet allografts

Autoimmunity

Cytokine or chemically derived nitric oxide alters the expression of proteins detected by two-dimensional gel electrophoresis in neonatal rat islets of Langerhans

Diabetes

Proteome analysis of interleukin-1 beta-induced changes in protein expression in rat islets of Langerhans

Diabetes

IL-1 induced protein changes in diabetes prone BB rat islets of Langerhans identified by proteome analysis

Diabetologia

Changes in expression of IL-1β influenced proteins in transplanted islets during development of diabetes in diabetes-prone BB-DP rats

Diabetologia

Galectins in cell growth and apoptosis

Cell. Mol. Life Sci.

Understanding the biochemical activities of galectin-1 and galectin-3 in the nucleus

Glycoconj. J.