Influence of a Cytomegalovirus Infection on Functions and Arachidonic Acid Metabolism of Rat Peritoneal Macrophages

Engels, W.; Grauls, Gert; Lemmens, P. J. M. R.; Mullers, W. J. H. A.; Bruggeman, Cathrien A.

doi:10.1002/jlb.45.5.466

Cited by 7 publications

(5 citation statements)

References 44 publications

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“…By analyzing the absolute numbers of pMF isolated by peritoneal lavage at different time points after infection, we showed that 1 day after infection the number of pMF present in the PC is significantly increased, most likely as a result of recruitment of mononuclear cells into the peritoneum. This increase in pMF numbers in response to RCMV infection was previously reported by Engels et al who moreover showed that this influx of mononuclear cells was preceded by an influx of polymorphonuclear granulocytes (PMN), reaching maximum numbers already 2 h after infection (Engels et al, 1989). At 1 day after infection we also observed increased numbers of PMN's, but the vast majority of isolated cells at this time point consisted of macrophages as determined by specific immunohistochemistry.…”

Section: Discussionsupporting

confidence: 88%

“…At all time points analyzed we could detect infected pMF using immunohistochemical detection of RCMV IE-antigens, although the percentages were low (, 0.05%). This suggests that almost no reproductive infection occurs in pMF (Engels et al, 1989). This does not exclude the possibility that many cells have taken up virus, however, without subsequent viral replication (i.e.…”

Section: Discussionmentioning

confidence: 94%

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Role of Peritoneal Macrophages in Cytomegalovirus‐induced Acceleration of Autoimmune Diabetes in BB‐rats

Hillebrands

Werf²,

Klatter³

et al. 2003

Journal of Immunology Research

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Background: As one of the natural perturbants, infection with cytomegalovirus (CMV) is believed to play a role in the development of Type I diabetes. Using the DP-BB rat model for autoimmune diabetes, we here report about possible mechanisms responsible for R(at)CMV-induced accelerated onset of diabetes.Methods: Rats were i.p. infected with 2 £ 10 6 plaque forming units (pfu) RCMV and followed for diabetes development. Presence of RCMV antigens and DNA was analyzed by immunohistochemistry and PCR on pancreatic tissue and isolated islets. The effect of viral infection on peritoneal macrophages (pMF) and diabetes development was studied by analyzing numbers of pMF, virus permissiveness and by depletion of this subset by peritoneal lavage.Results: RCMV accelerated onset of diabetes without infecting pancreatic islets. Immunohistochemistry and PCR on pancreas and isolated islets indicated that islets are non-permissive for RCMV. Infection results in an influx of pMF 1 day p.i. of which ,0.05% showed signs of reproductive infection. Depletion of pMF on days 1 -3 p.i. completely counteracted the accelerating effect of RCMV.Interpretation: RCMV accelerates onset of diabetes without infecting pancreatic islets. pMF might function as an carriage to disseminate virus to the pancreas where they enhance activation of autoreactive T cells resulting in accelerated onset of diabetes.Keywords: BB rats; Cytomegalovirus; Diabetes; Macrophages; RCMV; Virus INTRODUCTIONType 1 diabetes or Insulin Dependent Diabetes Mellitus (IDDM) (accounting for 10% of all cases of diabetes) is an organ-specific autoimmune disease, which results from the selective destruction of pancreatic b-cells. This destruction is histologically characterized by an inflammatory infiltrate around or within the islets (insulitis) containing large numbers of mononuclear cells and CD8 þ T cells (Notkins and Lernmark, 2001). Clinically, Type 1 diabetes presents as rapid onset polyuria, polydipsia, polyphagia, weight loss and hyperglycaemia .Although genetic factors are believed to be an important component in the pathogenesis of Type 1 diabetes (She, 1996;Field, 2002), also non-genetic factors appear to be required for disease onset since concordance rates among identical twins are only 30 -50% (Redondo et al., 2001). Among the non-genetic factors, viral infections are one of the leading candidate agents involved in the pathogenesis of Type 1 diabetes and a variety of different human viruses have been reported to be associated with human Type 1 diabetes, including CoxsackieB virus, rubella virus, mumps virus and several Herpesviridae (Jun and Yoon, 2001). Cytomegalovirus (CMV), a double stranded DNA virus belonging to the b-herpes virus family, is one of the Herpesviridae thought to be involved in the pathogenesis of Type 1 diabetes. This widespread virus (seropositivity varies from 60 to 90%) (Numazaki, 1997) causes latent and persistent infection without clinical symptoms in the immunocompetent host. In the immunocompromised host, however, primary infections and r...

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 94%

Role of Peritoneal Macrophages in Cytomegalovirus‐induced Acceleration of Autoimmune Diabetes in BB‐rats

Hillebrands

Werf²,

Klatter³

et al. 2003

Journal of Immunology Research

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“…However, perhaps mCMV-HC leads to levels of vascular NAD(P)H oxidase-derived ROS that are sufficient to induce platelet, but not leukocyte, adhesion, or mCMV-HC activates other pathways that overcome any anti-inflammatory effect of gp91 phox deficiency or apocynin treatment. There are conflicting reports about the induction of ROS by CMV in leukocytes [30–32], albeit these data were obtained during primary infection, and our data would suggest that if ROS are generated by leukocytes in response to mCMV-HC, NAD(P)H oxidase is not the primary source. The possibility remains that other oxidant-generating enzymes or dysregulation of antioxidant defenses in the vessel wall and/or circulating blood cells may mediate the venular inflammation in mCMV-HC mice.…”

Section: Discussionmentioning

confidence: 59%

“…Decreased O 2 ·− has been reported in CMV-infected macrophages [30] and neutrophils [31], whereas this virus has been show to elevate ROS generation in monocytes [32] and vascular smooth muscle cells [33]. Furthermore, responses differ between endothelial cells, in that human umbilical vein endothelial cells do not have altered ROS release upon CMV infection [34], but microvascular endothelial cells show enhanced intracellular oxidative stress under basal conditions, and exacerbated DMNQ-induced O 2 ·− generation [35].…”

Section: Introductionmentioning

confidence: 99%

NAD(P)H oxidase and eNOS play differential roles in cytomegalovirus infection-induced microvascular dysfunction

Leskov

Whitsett

Vásquez‐Vivar

et al. 2011

Free Radical Biology and Medicine

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Primary cytomegalovirus (CMV) infection promotes oxidative stress and reduces nitric oxide (NO) bioavailability in endothelial cells. These events are among the earliest vascular responses to cardiovascular risk factors. We assessed the roles of NAD(P)H oxidase and NO bioavailability in microvascular responses to persistent CMV infection alone or with hypercholesterolemia. Wildtype (WT) or gp91phox (NAD(P)H oxidase subunit) knockout mice received mock-inoculum or 3×104PFU murine CMV (mCMV) IP 5wks before placement on normal or high cholesterol diet (−HC) for 4wks before assessment of arteriolar function and venular blood cell recruitment using intravital microscopy. Some WT groups received sepiapterin (a precursor of the nitric oxide synthase co-factor, tetrahydrobiopterin), or apocynin (NAD(P)H oxidase inhibitor/antioxidant). Endothelium-dependent vasodilation was impaired in mCMV vs. mock WT, regardless of diet. This was not affected by sepiapterin, and pharmacological inhibition of nitric oxide synthase reduced dilation similarly in Mock and mCMV mice. Apocynin or deficiency of total, but not only blood cell or vascular wall (tested using bone marrow chimeras), gp91phox protected against arteriolar dysfunction. Blood cell recruitment was induced by mCMV-HC. Sepiapterin, but not NAD(P)H oxidase deficiency/apocynin, reduced leukocyte accumulation, whereas platelet adhesion was reduced by sepiapterin, apocynin or total, platelet-specific or vascular wall gp91phox-deficiency. These data implicate activation of both hematopoietic and vessel wall NAD(P)H oxidase in mCMV-induced arteriolar dysfunction, and platelet and vascular NAD(P)H oxidase in the thrombogenic phenotype induced by mCMV-HC. In contrast, findings with sepiapterin suggest eNOS dysfunction, perhaps uncoupling, mediates venular, but not arteriolar, responses to mCMV-HC, thus indicating that NAD(P)H oxidase and eNOS differentially regulate microvascular responses to mCMV.

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“…In vitro-studies indicate that CMV stimulates arachidonic acid metabolism [l] and that inhibitors of prostaglandin synthesis inhibit growth of CMV [21, 221. In one study, however, rat CMV infection was shown to decrease the number of arachidonic acid metabolites in peritoneal macrophages [6]. CMV immediate early proteins have been shown to transactivate the COX-2 gene, probably via NF-KB, and COX-2 has been reported to play an important role in the cell activation cascade induced by CMV, making the environment favorable for replication of the virus [21].…”

Section: Discussionmentioning

confidence: 99%

Induction of cyclo-oxygenase-2 by acute liver allograft rejection and cytomegalovirus infection in the rat

Martelius¹,

Wolff²,

Bruggeman³

et al. 2002

Transplant Int

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Cytomegalovirus (CMV)Keywords Cyclo-oxygenase-2 .infection has been shown to increase inflammation in rat liver allografts. In-vitro CMV has been shown to transactivate cyclo-oxygenase-2 (COX-2), while COX-2 plays a role in the CMV replication cycle. Our aim was to investigate the expression of COX-2 in liver allograft rejection and concomitant CMV infection. Expression of COX-2 was studied immunohistologically in rat liver allografts with or without rat CMV infection, in isografts, and in normal rat liver. There were small amounts of COX-2-positive mononuclear inflammatory cells in the normal liver and isografts. Acute rejection increased the amount of COX-2-expressing cells in the portal areas only, whereas concomitant CMV infection did this also in the sinusoid area. COX-2 may play a role in CMV infection in vivo as well. The possible role of COX-2 in the association between CMV infection and allograft rejection warrants further study. Liver rejection . Cytomegalovirus

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Influence of a Cytomegalovirus Infection on Functions and Arachidonic Acid Metabolism of Rat Peritoneal Macrophages

Cited by 7 publications

References 44 publications

Role of Peritoneal Macrophages in Cytomegalovirus‐induced Acceleration of Autoimmune Diabetes in BB‐rats

Role of Peritoneal Macrophages in Cytomegalovirus‐induced Acceleration of Autoimmune Diabetes in BB‐rats

NAD(P)H oxidase and eNOS play differential roles in cytomegalovirus infection-induced microvascular dysfunction

Induction of cyclo-oxygenase-2 by acute liver allograft rejection and cytomegalovirus infection in the rat

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