Deficiency of 5-Lipoxygenase Accelerates Renal Allograft Rejection in Mice

Goulet, Jennifer L.; Griffiths, Robert; Ruiz, Phillip; Mannon, Roslyn B.; Flannery, Pat; Platt, Jeffrey L.; Koller, Beverly H.; Coffman, Thomas M.

doi:10.4049/jimmunol.167.11.6631

Cited by 29 publications

(17 citation statements)

References 49 publications

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“…Previous reports have suggested a role of metabolites of the 5-lipoxygenase (5-LO) pathway and in particular the leukotrienes, in renal hemodynamics (Imig, 2000). Studies using 5-LO-deficient mice have also suggested a role for 5-LO metabolites in allograft rejection (Goulet et al, 2001); however, the precise role of 5-oxo-ETE and its receptor is not clear.…”

Section: Discussionmentioning

confidence: 97%

Expression and Characterization of a 5-oxo-6E,8Z,11Z,14Z-Eicosatetraenoic Acid Receptor Highly Expressed on Human Eosinophils and Neutrophils

et al. 2003

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Using a bioinformatics approach, we have isolated a novel Gprotein-coupled receptor (GPCR), R527, and have demonstrated that this receptor shows no significant homology to previously deorphanized GPCRs. Quantitative reverse transcription-polymerase chain reaction analysis of the expression of GPCR R527 indicated a very high level of mRNA expression in eosinophils, with high expression also detected in neutrophils and lung macrophages. Stable cell lines were generated expressing this receptor together with the G-protein ␣-subunit G␣ 16 . These cells were used to screen an agonist collection in a calcium mobilization assay and 5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid (5-oxo-ETE) was identified as a putative ligand. 5(S)-Hydroxyperoxy-6E,8Z,11Z,14Z-eicosatetraenoic acid was also shown to activate the receptor, whereas the leukotrienes LTB 4 , LTC 4 , LTD 4 , and LTE 4 failed to elicit a response. In cAMP assays, pertussis toxin reversed the inhibitory effects of 5-oxo-ETE on cAMP production, indicating that the receptor is G␣ i -coupled. The GPCR R527 shows pharmacological properties similar to those of the previously described 5-oxo-ETE receptor expressed on eosinophils, neutrophils, and monocytes. These cell types show chemotactic responses to 5-oxo-ETE, and this eicosanoid has been proposed to play a key role in the inflammatory response. The molecular identification of a receptor binding 5-oxo-ETE will expand our understanding of the physiological role of this mediator and may provide new therapeutic opportunities.

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Section: Discussionmentioning

confidence: 97%

Expression and Characterization of a 5-oxo-6E,8Z,11Z,14Z-Eicosatetraenoic Acid Receptor Highly Expressed on Human Eosinophils and Neutrophils

et al. 2003

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“…However, the contribution of 5-LOX metabolites to the regulation of the inflammatory response in more chronic settings of inflammation cannot be discounted. Indeed, there is evidence that the rejection of renal allografts is accelerated in 5-LOX Ϫ/Ϫ mice (Goulet et al, 2001).…”

Section: -Lipoxygenase In Renal I/r Injury 223mentioning

confidence: 99%

Reduction of Renal Ischemia-Reperfusion Injury in 5-Lipoxygenase Knockout Mice and by the 5-Lipoxygenase Inhibitor Zileuton

Patel¹,

Cuzzocrea²,

Chatterjee³

et al. 2004

Mol Pharmacol

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The role of 5-lipoxygenase (5-LOX) in the pathophysiology of renal ischemia/reperfusion (I/R) injury is not known. Here we investigate the effects of 1) the 5-LOX inhibitor zileuton and 2) 5-LOX gene knockout (5-LOX Ϫ/Ϫ ) mice on renal dysfunction and injury caused by I/R of the kidney in mice. Wild-type mice treated with zileuton (3 mg/kg i.v.) or 5-LOX Ϫ/Ϫ mice were subjected to bilateral renal artery occlusion (30 min) followed by reperfusion (24 h). Plasma urea, creatinine, and aspartate aminotransferase (AST) were measured as markers of renal dysfunction and reperfusion injury. Kidneys were used for histological evaluation of renal injury. Renal myeloperoxidase activity was measured and used as an indicator of polymorphonuclear leukocyte (PMN) infiltration and renal expression of intercellular adhesion molecule-1 (ICAM-1) was determined using immunohistochemistry. Administration of zileuton before I/R significantly reduced the degree of renal dysfunction (urea, creatinine) and injury (AST, histology). In addition, zileuton reduced the expression of ICAM-1 and the associated PMN infiltration caused by I/R of the mouse kidney. Compared with wild-type mice, the degree of renal dysfunction, injury, and inflammation caused by I/R in 5-LOX Ϫ/Ϫ mice was also significantly reduced, confirming the pathophysiological role of 5-LOX in the development of renal I/R injury. We propose that 1) endogenous 5-LOX metabolites enhance the degree of renal injury, dysfunction, and inflammation caused by I/R of the kidney by promoting the expression of adhesion molecules, and 2) inhibitors of 5-LOX may be useful in the treatment of conditions associated with I/R of the kidney.

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“…This is supported by the findings of Pinschewer et al, who demonstrated that FTY720 did not affect induction and expansion of cytotoxic T cells but caused a shift in distribution of lymphocytes from the spleen to the peripheral LNs (1). Conversely, failure of the contribution of the cysLT pathway to LN migration may be responsible for accelerated renal allograft rejection observed in 5-LO -/-mice (44). It is also possible that FTY720-driven homing to the LNs contributes to other aspects of immunosuppression.…”

mentioning

confidence: 99%

FTY720 stimulates multidrug transporter– and cysteinyl leukotriene–dependent T cell chemotaxis to lymph nodes

Honig¹,

Fu²,

Mao³

et al. 2003

J. Clin. Invest.

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IntroductionFTY720 is a synthetic sphingosine immunosuppressant that prolongs the survival of allografts without impairing normal T and B cell activation (1). In vitro studies have proposed that FTY720, like other sphingosine derivatives, may cause apoptotic death of the T cell, although the concentrations needed for this effect are greater than the normal therapeutic dose (2). FTY720 may also prolong graft survival by decreasing T cell infiltration into allografts or otherwise altering normal T cell trafficking. Recent studies demonstrate the disappearance of lymphocytes, especially T cells, from peripheral blood and spleen within 3-24 hours after a single oral dose of the drug. Concurrently, there is a marked increase in the number of lymphocytes in peripheral LNs, mesenteric LNs, and Peyer's patches (3). The LN sequestration of lymphocytes may be involved in the immunosuppressive effects of FTY720, as regulated trafficking of lymphocytes is necessary for systemic immune responses and allograft rejection (4, 5).A recent report demonstrates that FTY720 becomes phosphorylated in vivo and then acts as a potent agonist for multiple sphingosine-1-phosphate (S1P) receptors (S1PRs) (6). S1PR activation seems responsible for downstream events that lead to lymphocyte homing. However, the cellular and molecular mechanisms are not understood. Recent studies demonstrate a novel role for lipid mediators in LN homing of DCs. A blind screening of neutralizing mAb's led to the discovery that the lipid transporter ABCB1 (previously called MDR-1 and P-glycoprotein; for new nomenclature, see http://www.gene.ucl.ac.uk/nomenclature/genefamily/abc.html) regulates human DC migration to afferent lymphatics (7). Coupled with the hydrolysis of ATP, ABCB1 transports a wide range of compounds with various structures and targets, including ceramide analogs (8) and platelet-activating factor (9, 10), from the cytosol to the extracellular environment. A subsequent study demonstrated a role for another lipid transporter, Abcc1 (previously called Mrp1), in the migration of DCs to lymphatics. Abcc1 physiologically transports sphingolipid analogs and cysteinyl leukotriene C 4 (LTC 4 ), which is metabolized in the extracellular environment to LTD 4 and LTE 4 (11, 12). Mice lacking the Abcc1 gene show markedly decreased migration of Langerhans cells to LNs. Administration of exogenous cysteinyl leukotrienes (cysLTs) restores DC migration in these mice (13). These studies also demonstrate that both transporters are required for human DC migratory activity. However, whether the two transporters function in an interactive manner remains unclear (13,14).The mechanism by which Abcc1 causes LN homing of DCs was further shown to be chemokine-mediated. FTY720 is a sphingosine-derived immunosuppressant. Phosphorylated FTY720 promotes T cell homing from spleen and peripheral blood to LNs by acting as an agonist for sphingosine-1-phosphate (S1P) receptors. Here we demonstrate that FTY720 enhances the activity of the sphingosine transporter Abcb1 (Mdr1) and ...

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Deficiency of 5-Lipoxygenase Accelerates Renal Allograft Rejection in Mice

Cited by 29 publications

References 49 publications

Expression and Characterization of a 5-oxo-6E,8Z,11Z,14Z-Eicosatetraenoic Acid Receptor Highly Expressed on Human Eosinophils and Neutrophils

Expression and Characterization of a 5-oxo-6E,8Z,11Z,14Z-Eicosatetraenoic Acid Receptor Highly Expressed on Human Eosinophils and Neutrophils

Reduction of Renal Ischemia-Reperfusion Injury in 5-Lipoxygenase Knockout Mice and by the 5-Lipoxygenase Inhibitor Zileuton

FTY720 stimulates multidrug transporter– and cysteinyl leukotriene–dependent T cell chemotaxis to lymph nodes

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