Role of leukotrienes revealed by targeted disruption of the 5-lipoxygenase gene

Chen, Xinsheng; Sheller, James R.; Johnson, Eric N.; Funk, Colin D.

doi:10.1038/372179a0

Cited by 384 publications

(260 citation statements)

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“…Using 5LO-deficient mice of a mixed genetic background, we and others have shown that LT play an important role in AA-induced inflammatory responses (22,23). These studies also indicated that, while loss of 5LO decreased the edema and vascular permeability elicited by AA, a residual LT-insensitive response remained in the 5LO-deficient animals.…”

Section: Aa-induced Inflammation In 5lo-deficient Inbred Micementioning

confidence: 54%

“…Using these mouse lines, we and others have defined a role for LT in several models of acute inflammation (22)(23)(24). However, these studies revealed variability in both the intensity of inflammatory responses in wild-type mice and the extent to which loss of LT production affected these responses.…”

mentioning

confidence: 99%

“…A direct means of determining the contribution of LT to an inflammatory response was made available by the generation of mouse lines deficient in either the 5LO enzyme or the 5-lipoxygenase-activating protein (22)(23)(24)(25). Using these mouse lines, we and others have defined a role for LT in several models of acute inflammation (22)(23)(24).…”

mentioning

confidence: 99%

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Genetic Factors Determine the Contribution of Leukotrienes to Acute Inflammatory Responses

Goulet

Byrum

Key

et al. 2000

The Journal of Immunology

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Leukotrienes (LT) are potent lipid mediators synthesized by the 5-lipoxygenase pathway of arachidonic acid (AA) metabolism. LT have been implicated in a broad spectrum of inflammatory processes. To investigate the influence of genetic factors on the contribution of LT to acute inflammation, we generated congenic 5-lipoxygenase-deficient 129, C57BL/6 (B6), and DBA/1Lac (DBA) mouse lines. Topical application of AA evoked a vigorous inflammatory response in 129 and DBA mice, whereas only a modest response was seen in B6 animals. The response to AA in 129 and DBA strains is LT dependent. In contrast, LT make little contribution to this response in B6 mice. AA-induced inflammation in B6 mice is prostanoid dependent, since this response was substantially reduced by treating B6 mice with a cyclooxygenase inhibitor. These data suggest that prostanoids are essential for AA-induced cutaneous inflammation in B6 mice, whereas LT are the major mediators of this response in 129 and DBA strains. In contrast, the response to AA in the peritoneal cavity is robust in the 129 and B6 strains, but was significantly blunted in DBA mice, showing that strain differences in the response to AA are tissue specific. Variations in these and other experimental models of inflammation appear to correlate directly with the ability of a particular mouse strain and a specific tissue to respond to LT, specifically LTC4. Taken together, these findings indicate that the relative contribution of prostanoids and LT to inflammatory responses is variable not only between strains but also between different tissues within these inbred mouse lines.

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Section: Aa-induced Inflammation In 5lo-deficient Inbred Micementioning

confidence: 54%

mentioning

confidence: 99%

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Genetic Factors Determine the Contribution of Leukotrienes to Acute Inflammatory Responses

Goulet

Byrum

Key

et al. 2000

The Journal of Immunology

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“…C57BL/6, fvb, C57BL/6 CD62L -/- (15), B6/129 5-LO -/- (16), and B6/129 hybrid mice 8-10 weeks of age were purchased from The Jackson Laboratory (Bar Harbor, Maine, USA). Fvb Abcb1 -/-(17) mice were purchased from Taconic Laboratories (Germantown, New York, USA).…”

Section: Methodsmentioning

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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“…Previously, LT generation was thought to be regulated largely by the amount of either 5-LO or FLAP protein present in the source cell. More recently, the discovery that 5-LO can occur in both the cytosol and the nucleus of resting cells [5,12,16,22] presented the possibility that compartmentation of 5-LO can regulate LT synthetic capacity. This study underlines the importance of other processes, including translocation, inactivation and persistent membrane association, in 5-LO action.…”

Section: Discussionmentioning

confidence: 99%

Capacity for repeatable leukotriene generation after transient stimulation of mast cells and macrophages

Brock

McNISH

Peters‐Golden

1998

Biochemical Journal

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Leukotriene (LT) synthesis is initiated by the enzyme 5-lipoxygenase (5-LO). Prolonged cell stimulation causes the translocation of 5-LO to the nuclear envelope and the synthesis of LT, with subsequent inactivation and persistent membrane association of 5-LO. In this study, we examined whether persistent membrane association of 5-LO, as well as the inactivation of 5-LO, could be prevented by shortening the length of cell stimulation or by blocking LT synthesis. As expected, stimulation of rat basophilic leukaemia (RBL) cells, a mast cell model, or alveolar macrophages (AMs) with calcium ionophore for 15 min caused 5-LO translocation, LT generation and the inactivation and persistent membrane association of 5-LO. When RBL cells or AMs instead were stimulated for 0.5-5 min, translocation of 5-LO and synthesis of LT still occurred. However, after washing and resting, the 5-LO enzyme returned to its original intracellular distribution. Furthermore these cells showed a retained capacity

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Role of leukotrienes revealed by targeted disruption of the 5-lipoxygenase gene

Cited by 384 publications

References 18 publications

Genetic Factors Determine the Contribution of Leukotrienes to Acute Inflammatory Responses

Genetic Factors Determine the Contribution of Leukotrienes to Acute Inflammatory Responses

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

Capacity for repeatable leukotriene generation after transient stimulation of mast cells and macrophages

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