Adenovirus Transduction Induces Expression of Multiple Chemokines and Chemokine Receptors in Murine β Cells and Pancreatic Islets

Zhang, Nan; Schröppel, Bernd; Chen, Dongmei; Fu, Shuang; Hudkins, Kelly L.; Zhang, Haojiang; Murphy, Barbara; Sung, Randall S.; Bromberg, Jonathan S.

doi:10.1046/j.1600-6143.2003.00215.x

Cited by 49 publications

(55 citation statements)

References 47 publications

(47 reference statements)

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“…However, here we present evidence of an alternative role for CCL5, namely to influence normal beta cell function via GPR75 activation. Ccl5 mRNA and protein have been identified in islets from non-diabetic BALB/c [6] and C57BL/6 mice [31], and we have confirmed expression of this chemokine in islets isolated from ICR mice and from healthy human donors. We found that CCL5 was constitutively expressed by mouse and human islet cells, although cellular localisation varied between the two species, with CCL5 being expressed primarily by alpha cells in mouse islets, while being detected in alpha and in beta cells in human islets.…”

Section: Discussionsupporting

confidence: 74%

The novel chemokine receptor, G-protein-coupled receptor 75, is expressed by islets and is coupled to stimulation of insulin secretion and improved glucose homeostasis

et al. 2013

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Aims/hypothesis Chemokine (C-C motif) ligand 5 (CCL5) acts at C-C chemokine receptors (CCRs) to promote immune cell recruitment to sites of inflammation, but is also an agonist at G-protein-coupled receptor 75 (GPR75), which has very limited homology with CCRs. GPR75 is coupled to Gq to elevate intracellular calcium, so we investigated whether islets express this receptor and whether its activation by CCL5 increases beta cell calcium levels and insulin secretion. Methods Islet CCL5 receptor mRNA expression was measured by quantitative RT-PCR and GPR75 was detected in islets by western blotting and immunohistochemistry. In some experiments GPR75 was downregulated by transient transfection with small interfering RNA. Real-time changes in intracellular calcium were determined by single-cell microfluorimetry. Dynamic insulin secretion from perifused islets was quantified by radioimmunoassay. Glucose homeostasis in lean and obese mice was determined by measuring glucose and insulin tolerance, and insulin secretion in vivo. Results Mouse and human islets express GPR75 and its ligand CCL5. Exogenous CCL5 reversibly increased intracellular calcium in beta cells via GPR75, this phenomenon being dependent on phospholipase C activation and calcium influx. CCL5 also stimulated insulin secretion from mouse and human islets in vitro, and improved glucose tolerance in lean mice and in a mouse model of hyperglycaemia and insulin resistance (ob/ob ). The improvement in glucose tolerance was associated with enhanced insulin secretion in vivo, without changes in insulin sensitivity. Conclusions/interpretation Although CCL5 is implicated in the pathogenesis of diabetes through activation of CCRs, it has beneficial effects on beta cells through GPR75 activation.

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Section: Discussionsupporting

confidence: 74%

The novel chemokine receptor, G-protein-coupled receptor 75, is expressed by islets and is coupled to stimulation of insulin secretion and improved glucose homeostasis

et al. 2013

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“…5-2. islets in response to adenovirus vector transduction parallels mRNA expression detected by the same cDNA array (38). Thus, we have found the pathway-specific cDNA array to be a reliable technique to investigate the expression of multiple genes simultaneously.…”

Section: Discussionmentioning

confidence: 86%

Differential Chemokine and Chemokine Receptor Gene Induction by Ischemia, Alloantigen, and Gene Transfer in Cardiac Grafts

Chen

Ding

Schröppel

et al. 2003

American Journal of Transplantation

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Transplantation of allogeneic grafts presents several challenges to the innate and adaptive immune systems including chemokine leukocyte recruitment, activation, and effector function. We defined the chemokines and receptors induced by the transplant procedure/ischemia injury, alloantigen and gene transfer vector administration in murine cardiac grafts. E1, E3 deleted AdRSVbgal was transferred into grafts at the time of transplantation, grafts were harvested after 1-14 days, and a pathway-specific cDNA array was used to evaluate the levels of 67 chemokine and chemokine receptor genes. Transplantation resulted in ischemic injury and induction of a number of similar genes in both the syngeneic and allogeneic grafts, such as CXCL1 and CXCL5, which increased dramatically on day 1 and returned rapidly to baseline in the syngeneic grafts. Alloantigen stimulated the adaptive immune response and induced the presence of more inflammatory genes within the grafts, particularly at later time points. The adenovirus vector induced a broader panel of genes, among them potent inflammatory chemokines CXCL9 and CXCL10, that are induced earlier or more strongly compared with alloantigen stimulation alone. As alloantigen and adenovirus vectors both induce similar sets of genes, targeting these molecules may not only inhibit alloimmunity, but also enhance the utility of the gene transfer vector.

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“…50 Several studies have previously demonstrated improved islet graft revascularization in response to the production of recombinant VEGF-A within the islets. 8,9 However, unlike other pretreatment procedures for introducing VEGF-A to the islets, such as gene therapy, 8,9,51 anchoring VEGF-A directly to immobilized heparin on the islet surface should not be associated with an increased risk of inducing adverse effects on islet function 52,53 or adaptive immune responses. Importantly, islet functionality was not affected by anchoring of VEGF-A in this study because the growth factor in combination with immobilized heparin did not affect insulin release in response to a glucose challenge.…”

Section: Figmentioning

confidence: 99%

Anchoring of Vascular Endothelial Growth Factor to Surface-Immobilized Heparin on Pancreatic Islets: Implications for Stimulating Islet Angiogenesis

Cabric

Sánchez

Johansson

et al. 2010

Tissue Engineering Part A

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Adenovirus Transduction Induces Expression of Multiple Chemokines and Chemokine Receptors in Murine β Cells and Pancreatic Islets

Cited by 49 publications

References 47 publications

The novel chemokine receptor, G-protein-coupled receptor 75, is expressed by islets and is coupled to stimulation of insulin secretion and improved glucose homeostasis

The novel chemokine receptor, G-protein-coupled receptor 75, is expressed by islets and is coupled to stimulation of insulin secretion and improved glucose homeostasis

Differential Chemokine and Chemokine Receptor Gene Induction by Ischemia, Alloantigen, and Gene Transfer in Cardiac Grafts

Anchoring of Vascular Endothelial Growth Factor to Surface-Immobilized Heparin on Pancreatic Islets: Implications for Stimulating Islet Angiogenesis

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