Transcriptional Regulation of Chemokine Genes: A Link to Pancreatic Islet Inflammation?

Burke, Susan J.; Collier, J. Jason

doi:10.3390/biom5021020

Cited by 25 publications

(32 citation statements)

References 96 publications

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“…With many discrete chemokines made in response to IL-1␤ and IFN␥ in pancreatic ␤-cells (8,44), the ␤-cell influence on tissue leukocytosis and overall pancreatic inflammatory responses may be underappreciated. It also appears that NF-B is the major regulatory factor controlling chemokine production in response to IL-1␤ (9,10,12), whereas STAT1 is the predominant transcription factor mediating the increased chemokine production by IFN␥ (9, 12).…”

Section: Discussionmentioning

confidence: 99%

“…In pancreatic ␤-cells, nitric oxide influences insulin secretion, DNA damage and repair, and overall cellular viability. In addition to controlling the abundance of iNOS, IL-1␤ also promotes increased production of a variety of chemokines (8,44), which are soluble secreted factors that regulate immune cell recruitment and activation (25).…”

mentioning

confidence: 99%

“…MCP-1) is elevated in islets isolated from diabetic mice (8) and from human islets exposed to cytokines (21,44). Transgenic mice with CCL2 production driven within pancreatic ␤-cells display enhanced recruitment of immune cells into the pancreatic islets, although disease outcome differs depending on genetic background (35,36).…”

mentioning

confidence: 99%

“…Interestingly, CCL2, CCL20, and iNOS are all bona fide target genes controlled by the NF-B family of transcription factors (8,11,13). NF-B subunits include p65 (RelA), RelB, c-Rel, p50 (NF-B1), and p52 (NF-B2).…”

mentioning

confidence: 99%

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IL-1β reciprocally regulates chemokine and insulin secretion in pancreatic β-cells via NF-κB

Burke

Stadler

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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Proinflammatory cytokines impact islet ␤-cell mass and function by altering the transcriptional activity within pancreatic ␤-cells, producing increases in intracellular nitric oxide abundance and the synthesis and secretion of immunomodulatory proteins such as chemokines. Herein, we report that IL-1␤, a major mediator of inflammatory responses associated with diabetes development, coordinately and reciprocally regulates chemokine and insulin secretion. We discovered that NF-B controls the increase in chemokine transcription and secretion as well as the decrease in both insulin secretion and proliferation in response to IL-1␤. Nitric oxide production, which is markedly elevated in pancreatic ␤-cells exposed to IL-1␤, is a negative regulator of both glucose-stimulated insulin secretion and glucose-induced increases in intracellular calcium levels. By contrast, the IL-1␤-mediated production of the chemokines CCL2 and CCL20 was not influenced by either nitric oxide levels or glucose concentration. Instead, the synthesis and secretion of CCL2 and CCL20 in response to IL-1␤ were dependent on NF-B transcriptional activity. We conclude that IL-1␤-induced transcriptional reprogramming via NF-B reciprocally regulates chemokine and insulin secretion while also negatively regulating ␤-cell proliferation. These findings are consistent with NF-B as a major regulatory node controlling inflammation-associated alterations in islet ␤-cell function and mass. chemokine; inflammation; insulin secretion; interleukin-1; nitric oxide THE PROGRESSION TO BOTH TYPE 1 (T1DM) and type 2 diabetes mellitus (T2DM) proceeds via immune cell-associated alterations in islet ␤-cell mass and function. Alterations in islet ␤-cell mass and function are two major determinants controlling the total amount of insulin produced and secreted in response to physiological stimuli (e.g., glucose). Proinflammatory cytokines such as IL-1␤ and IFN␥ contribute significantly to losses in islet ␤-cell viability and insulin secretion. Islet

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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IL-1β reciprocally regulates chemokine and insulin secretion in pancreatic β-cells via NF-κB

Burke

Stadler

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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“…EGR1 is involved in cell growth, cell differentiation and cell survival [45]. EGR1 is expressed in T-cells and promotes T-cell activation and development by transcriptional induction of key cytokines, such as IL-2 and TNF-α, and costimulatory molecules, such as CD40 ligand, after T-cell receptor (TCR) stimulation [46, 22].…”

Section: Discussionmentioning

confidence: 99%

Atorvastatin inhibits the immediate-early response gene EGR1 and improves the functional profile of CD4⁺T-lymphocytes in acute coronary syndromes

et al. 2017

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Background- Adaptive immune-response is associated with a worse outcome in acute coronary syndromes. Statins have anti-inflammatory activity beyond lowering lipid levels. We investigated the effects of ex-vivo and in-vivo atorvastatin treatment in acute coronary syndromes on CD4+T-cells, and the underlying molecular mechanisms.Approach and results- Blood samples were collected from 50 statin-naïve acute coronary syndrome patients. We assessed CD4+T-cell activation by flow-cytometry, the expression of 84 T-helper transcription-factors and 84 T-cell related genes by RT-qPCR, and protein expression by Western-blot, before and after 24-hours incubation with increasing doses of atorvastatin: 3-10-26 g/ml (corresponding to blood levels achieved with doses of 10-40-80 mg, respectively). After incubation, we found a significant decrease in interferon-?-producing CD4+CD28nullT-cells (P = 0.009) and a significant increase in interleukin-10-producing CD4+CD25highT-cells (P < 0.001). Atorvastatin increased the expression of 2 genes and decreased the expression of 12 genes (in particular, EGR1, FOS,CCR2 and toll like receptor-4; >3-fold changes).The in-vivo effects of atorvastatin were analyzed in 10 statin-free acute coronary syndrome patients at baseline, and after 24h and 48h of atorvastatin therapy (80 mg/daily): EGR1-gene expression decreased at 24h (P = 0.01) and 48h (P = 0.005); EGR1-protein levels decreased at 48h (P = 0.03).Conclusions-In acute coronary syndromes, the effects of atorvastatin on immune system might be partially related to the inhibition of the master regulator gene EGR1. Our finding might offer a causal explanation on why statins improve the early outcome in acute coronary syndromes.

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Pancreatic β‐Cell production of CXCR3 ligands precedes diabetes onset

et al. 2016

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Type 1 diabetes mellitus (T1DM) results from immune cell-mediated reductions in function and mass of the insulin-producing β-cells within the pancreatic islets. While the initial trigger(s) that initiates the autoimmune process is unknown, there is a leukocytic infiltration that precedes islet β-cell death and dysfunction. Herein, we demonstrate that genes encoding the chemokines CXCL9, 10, and 11 are primary response genes in pancreatic β-cells and are also elevated as part of the inflammatory response in mouse, rat, and human islets. We further established that STAT1 participates in the transcriptional control of these genes in response to the pro-inflammatory cytokines IL-1β and IFN-γ. STAT1 is phosphorylated within five minutes after β-cell exposure to IFN-γ, with subsequent occupancy at proximal and distal response elements within the Cxcl9 and Cxcl11 gene promoters. This increase in STAT1 binding is coupled to the rapid appearance of chemokine transcript. Moreover, circulating levels of chemokines that activate CXCR3 are elevated in non-obese diabetic (NOD) mice, consistent with clinical findings in human diabetes. We also report herein that mice with genetic deletion of CXCR3 (receptor for ligands CXCL9, 10, and 11) exhibit a delay in diabetes development after being injected with multiple low doses of streptozotocin. Therefore, we conclude that production of CXCL9, 10, and 11 from islet β-cells controls leukocyte migration and activity into pancreatic tissue, which ultimately influences islet β-cell mass and function.

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Transcriptional Regulation of Chemokine Genes: A Link to Pancreatic Islet Inflammation?

Cited by 25 publications

References 96 publications

IL-1β reciprocally regulates chemokine and insulin secretion in pancreatic β-cells via NF-κB

IL-1β reciprocally regulates chemokine and insulin secretion in pancreatic β-cells via NF-κB

Atorvastatin inhibits the immediate-early response gene EGR1 and improves the functional profile of CD4⁺T-lymphocytes in acute coronary syndromes

Pancreatic β‐Cell production of CXCR3 ligands precedes diabetes onset

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Transcriptional Regulation of Chemokine Genes: A Link to Pancreatic Islet Inflammation?

Cited by 25 publications

References 96 publications

IL-1β reciprocally regulates chemokine and insulin secretion in pancreatic β-cells via NF-κB

IL-1β reciprocally regulates chemokine and insulin secretion in pancreatic β-cells via NF-κB

Atorvastatin inhibits the immediate-early response gene EGR1 and improves the functional profile of CD4+T-lymphocytes in acute coronary syndromes

Pancreatic β‐Cell production of CXCR3 ligands precedes diabetes onset

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Atorvastatin inhibits the immediate-early response gene EGR1 and improves the functional profile of CD4⁺T-lymphocytes in acute coronary syndromes