Genetic Factors Determine the Contribution of Leukotrienes to Acute Inflammatory Responses

Goulet, Jennifer L.; Byrum, Robert S.; Key, Mikelle L.; Nguyen, MyTrang; Wagoner, Victoria A.; Koller, Beverly H.

doi:10.4049/jimmunol.164.9.4899

Cited by 26 publications

(29 citation statements)

References 38 publications

(59 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We have previously reported that macrophages from 5-LO-deficient animals released increased amounts of PGE 2 and TXB 2 , compared with wild-type controls (30), and we found an enhanced role for prostanoids in several acute inflammatory processes in 5-LO-deficient mice (30,32). Furthermore, several studies have demonstrated enhanced production of COX metabolites, specifically TXB 2 , in rat (5, 10, 41) and dog (10, 42) models of allograft rejection, and that TXB 2 contributes to transplant rejection (4,5,8,10).…”

Section: Discussionsupporting

confidence: 64%

“…Additional studies have demonstrated that the loss of 5-LO may result in enhanced synthesis and activity of other eicosanoids, particularly COX metabolites (30,32). Therefore, we explored the possibility that eicosanoid production may be altered in 5-LO-deficient allografts by measuring levels of TXB 2 (the stable metabolite of TXA 2 ) in cortical homogenates prepared from the transplanted kidneys and stimulated with the calcium ionophore A23187.…”

Section: Resultsmentioning

confidence: 99%

“…The generation of 5-LO-deficient mice has been previously described (30,32). The 5lo Ϫ/Ϫ mice and corresponding wild-type animals are on an inbred 129 (H-2 b ) genetic background.…”

Section: Micementioning

confidence: 99%

See 2 more Smart Citations

Deficiency of 5-Lipoxygenase Accelerates Renal Allograft Rejection in Mice

Goulet

Griffiths

Ruiz

et al. 2001

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Acute renal allograft rejection is associated with alterations in renal arachidonic acid metabolism, including enhanced synthesis of leukotrienes (LTs). LTs, the products of the 5-lipoxygenase (5-LO) pathway, are potent lipid mediators with a broad range of biologic activities. Previous studies, using pharmacological agents to inhibit LT synthesis or activity, have implicated these eicosanoids in transplant rejection. To further investigate the role of LTs in acute graft rejection, we transplanted kidneys from CByD2F1 mice into fully allogeneic 129 mice that carry a targeted mutation in the 5lo gene. Unexpectedly, allograft rejection was significantly accelerated in 5-LO-deficient mice compared with wild-type animals. Despite the marked reduction in graft survival, the 5lo mutation had no effect on the hemodynamics or morphology of the allografts. Although LTB4 levels were reduced, renal thromboxane B2 production and cytokine expression were not altered in 5-LO-deficient allograft recipients. These findings suggest that, along with their proinflammatory actions, metabolites of 5-LO can act to enhance allograft survival.

show abstract

Section: Discussionsupporting

confidence: 64%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Deficiency of 5-Lipoxygenase Accelerates Renal Allograft Rejection in Mice

Goulet

Griffiths

Ruiz

et al. 2001

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Because inflammatory responses to leukotrienes have been previously shown to differ among mouse strains with different genetic backgrounds, 22 two strains of apoE Ϫ/Ϫ mice on a C57B/6 background (C57E Ϫ/Ϫ ) and apoE Ϫ/Ϫ mice on a mixed background of 1290la/BalbC (129E Ϫ/Ϫ ), and LDLr Ϫ/Ϫ mice on a C57B/6 background were treated with a LTB4 antagonist (CP-105,696). The two different strains of apoE Ϫ/Ϫ (C57E…”

Section: Analysis Of Lesionsmentioning

confidence: 99%

Leukotriene B4 Receptor Antagonism Reduces Monocytic Foam Cells in Mice

Aiello

Bourassa

Lindsey

et al. 2002

ATVB

215

144

View full text Add to dashboard Cite

Abstract-Leukotriene B4 (LTB4) is a potent chemotactic agent that activates monocytes through the LTB4 receptor (BLTR). We tested the hypothesis that LTB4 receptor blockade would slow atherosclerotic progression by inhibiting monocyte recruitment. Homozygous low-density receptor knockout (LDLr Ϫ/Ϫ ) mice and apolipoprotein E deficient (apoE Ϫ/Ϫ ) mice were treated with a specific LTB4 receptor antagonist, CP-105,696, for 35 days. In apoE Ϫ/Ϫ mice, treatment with the LTB4 antagonist did not affect plasma lipid concentrations but significantly reduced CD11b levels both in vascular lesions and whole blood. Compared with age-matched controls, lipid accumulation and monocyte infiltration were significantly reduced in treated apoE Ϫ/Ϫ mice at all time points tested. Lesion area reduction was also demonstrated in LDLr Ϫ/Ϫ mice maintained on a high-fat diet. LTB4 antagonism had no significant effect on lesion size in mice possessing the null alleles for another chemotactic agent, monocyte chemoattractant protein-1 (MCP-1 Key Words: leukotriene B4 Ⅲ atherosclerosis Ⅲ monocyte chemoattractant protein-1 T he pathogenesis of atherosclerosis is a complex process, which involves the recruitment and activation of monocytes in the developing atherosclerotic lesion. 1 It is thought to initiate when circulating monocytes are first attracted to a site of vascular injury through the upregulation of adhesion molecules and chemotactic factors in the lesion. 2,3 Once attached to the vessel wall, monocytes, attracted by a gradient of chemotactic factors, migrate between the endothelial cells into the subendothelial space where they differentiate into macrophages and become lipid-laden foam cells. 2 A growing body of evidence suggests that the recruitment of monocytes is governed by cell-specific chemoattractants. Several molecules have chemotactic activity for monocytes, including N-formylmethionyl peptides exemplified by N-formylmethionyl-leucyl-phenylalanine (FMLP), the complement fragment C5a, the arachidonic acid metabolite leukotriene B4 (LTB4), 12-hydroxyeicosatetraenoic acid (12-HETE), and the chemoattractant monocyte chemotactic protein-1 (MCP-1). 4See page 361 and cover MCP-1 is the prototype of the CC chemokine ␤ subfamily and exhibits the most potent chemotactic activity for monocytes. 5 MCP-1 is highly expressed in human atheromatous plaques, 6 and its overexpression contributes to the development of atherosclerosis in mouse models. 7 In hypercholesterolemic mice, a deficiency in either MCP-1 8 or the MCP-1 receptor (CCR2) 9 results in a marked decrease in atheromas and fewer monocytes in vascular lesions. However, at later stages of lesion development in these mice, differences in lesion size relative to wild type become less pronounced. These data suggest that other chemotactic factors are likely compensating for the lack of MCP-1.LTB4, a product of the 5-lipoxygenase pathway of arachidonic acid metabolism, is also a potent chemoattractant and proinflammatory mediator thought to be involved in the pathogenesis of several ...

show abstract

“…We chose 129 inbred strain because Goulet et al (32) CysLTs were detected in epidermis (data not shown). In the subcutaneous connective tissues, however, high expressions of CysLT 1 (Fig.…”

Section: Different Tissue Distribution Of Cyslt 1 and Cyslt 2 Mrna Inmentioning

confidence: 99%

Characterization of Mouse Cysteinyl Leukotriene Receptors mCysLT1 and mCysLT2

Ogasawara¹,

Ishii²,

Yokomizo³

et al. 2002

Journal of Biological Chemistry

View full text Add to dashboard Cite

Cysteinyl leukotrienes (LTs) are important proinflammatory mediators. Their precise roles in mice need to be elucidated to interpret mouse models of inflammatory diseases. For this purpose, we cloned and characterized mouse receptors for cysteinyl LTs, mCysLT 1 and mCysLT 2 . mCysLT 1 and mCysLT 2 were composed of 339 amino acids with 87.3% identity and 309 amino acids with 73.4% identity to human orthologues, respectively. A pharmacological difference was noted between mouse and human CysLT 2 . Pranlukast, a specific inhibitor for human CysLT 1 , antagonized mCysLT 2 responses as determined by Ca 2؉ elevation and receptor-induced promoter activation. The mRNA expressions of both mCysLTs were higher in C57BL/6 mice than in 129 mice. mCysLT 1 mRNA was expressed mainly in skin, lung, and small intestine. mCysLT 2 was seen more ubiquitously with high expressions in spleen, lung, and small intestine. By in situ hybridization we demonstrated for the first time that mCysLT 1 and mCysLT 2 were expressed in subcutaneous fibroblasts. The different pharmacological characteristics of CysLT 2 between human and mouse and the different distributions of CysLTs between mouse strains suggest that careful choice and interpretation are necessary for a study of CysLTs using animal models.

show abstract

Genetic Factors Determine the Contribution of Leukotrienes to Acute Inflammatory Responses

Cited by 26 publications

References 38 publications

Deficiency of 5-Lipoxygenase Accelerates Renal Allograft Rejection in Mice

Deficiency of 5-Lipoxygenase Accelerates Renal Allograft Rejection in Mice

Leukotriene B4 Receptor Antagonism Reduces Monocytic Foam Cells in Mice

Characterization of Mouse Cysteinyl Leukotriene Receptors mCysLT1 and mCysLT2

Contact Info

Product

Resources

About