The leukotriene E4 puzzle: Finding the missing pieces and revealing the pathobiologic implications

Austen, K. Frank; Maekawa, Akiko; Kanaoka, Yoshihide; Boyce, Joshua A.

doi:10.1016/j.jaci.2009.05.046

Cited by 94 publications

(78 citation statements)

References 41 publications

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“…12 Leukotriene C 4 (LTC 4 ), a member of the cysteinyl leukotriene family (CysLT), is a potent pro-inflammatory lipid mediator, produced by inflammatory cells such as mast cells, eosinophils, basophils and macrophages. 13,14 It is a potent spasmogen and vasoconstrictor, promotes mucus secretion, and together with histamine is a known immunomodulatory agent of allergic and inflammatory Carolina Alvarez, 1 María M. Amaral, 1 Cecilia Langellotti 2 and Mó nica Vermeulen 1 1 …”

Section: Introductionmentioning

confidence: 99%

Leukotriene C4 prevents the complete maturation of murine dendritic cells and modifies interleukin-12/interleukin-23 balance

Álvarez¹,

Amaral²,

Langellotti³

et al. 2011

Immunology

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Summary Leukotriene C4 is an important mediator in the development of inflammatory reactions and ischaemia. Previous studies have shown that leukotriene C4 is able to modulate the function of dendritic cells (DCs) and induce their chemotaxis from skin to lymph node. In this study, we decided to evaluate the modulation exerted by leukotriene C4 on DCs, depending on their status of activation. We showed for the first time that leukotriene C4 stimulates endocytosis both in immature and lipopolysaccharide (LPS) ‐activated DCs. Moreover, it suppressed the interleukin‐12p70 (IL‐12p70) release, but induces the secretion of IL‐23 by DCs activated with LPS and promotes the expansion of T helper type 17 (Th17) lymphocytes. Furthermore, blocking the release of IL‐23 reduced the percentages of CD4+ T cells producing IL‐17 in a mixed lymphocyte reaction. Ours results suggest that leukotriene C4 interferes with the complete maturation of inflammatory DCs in terms of phenotype and antigen uptake, while favouring the release of IL‐23, the main cytokine involved in the maintenance of the Th17 profile.

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Section: Introductionmentioning

confidence: 99%

Leukotriene C4 prevents the complete maturation of murine dendritic cells and modifies interleukin-12/interleukin-23 balance

Álvarez¹,

Amaral²,

Langellotti³

et al. 2011

Immunology

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“…Leukotriene C 4 (LTC 4 ), 2 LTD 4 , and LTE 4 , collectively called cysteinyl leukotrienes (cys-LTs), are proinflammatory mediators derived from arachidonic acid through the 5-lipoxygenase/ LTC 4 synthase pathway (1,2). Intracellularly synthesized LTC 4 is exported via multidrug resistance-associated proteins and is rapidly metabolized in the extracellular space by cleavage removal of glutamic acid and then glycine to LTD 4 and LTE 4 , respectively.…”

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confidence: 99%

Identification of GPR99 Protein as a Potential Third Cysteinyl Leukotriene Receptor with a Preference for Leukotriene E4 Ligand

Kanaoka

Maekawa

Austen

2013

Journal of Biological Chemistry

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154

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Background: A most stable cysteinyl leukotriene, LTE 4 , mediates vascular permeability in mice lacking the two known receptors. Results: GPR99 deficiency abolishes LTE 4 -induced vascular permeability in mice also lacking the two known receptors. Conclusion: GPR99 is a potential third cysteinyl leukotriene receptor. Significance: GPR99 may be a therapeutic target for inflammatory diseases.The cysteinyl leukotrienes (cys-LTs), leukotriene C 4 (LTC 4 ), a conjugation product of glutathione and eicosatetraenoic acid, and its metabolites, LTD 4 and LTE 4 , are lipid mediators of smooth muscle constriction and inflammation in asthma. LTD 4 is the most potent ligand for the type 1 cys-LT receptor (CysLT 1 R), and LTC 4 and LTD 4 have similar lesser potency for CysLT 2 R, whereas LTE 4 has little potency for either receptor. Cysltr1/Cysltr2 ؊/؊ mice, lacking the two defined receptors, exhibited a comparable dose-dependent vascular leak to intradermal injection of LTC 4 or LTD 4 and an augmented response to LTE 4 as compared with WT mice. As LTE 4 retains a cysteine residue and might provide recognition via a dicarboxylic acid structure, we screened cDNAs within the P2Y nucleotide receptor family containing CysLTRs and dicarboxylic acid receptors with trans-activator reporter gene assays. GPR99, previously described as an oxoglutarate receptor (Oxgr1), showed both a functional and a binding response to LTE 4 in these transfectants. We generated Gpr99 ؊/؊ and Gpr99/Cysltr1/Cysltr2 ؊/؊ mice for comparison with WT and Cysltr1/Cysltr2 ؊/؊ mice. Strikingly, GPR99 deficiency in the Cysltr1/Cysltr2 ؊/؊ mice virtually eliminated the vascular leak in response to the cys-LT ligands, indicating GPR99 as a potential CysLT 3 R active in the Cysltr1/Cysltr2 ؊/؊ mice. Importantly, the Gpr99 ؊/؊ mice showed a dose-dependent loss of LTE 4 -mediated vascular permeability, but not to LTC 4 or LTD 4 , revealing a preference of GPR99 for LTE 4 even when CysLT 1 R is present. As LTE 4 is the predominant cys-LT species in inflamed tissues, GPR99 may provide a new therapeutic target.Leukotriene C 4 (LTC 4 ), 2 LTD 4 , and LTE 4 , collectively called cysteinyl leukotrienes (cys-LTs), are proinflammatory mediators derived from arachidonic acid through the 5-lipoxygenase/ LTC 4 synthase pathway (1, 2). Intracellularly synthesized LTC 4 is exported via multidrug resistance-associated proteins and is rapidly metabolized in the extracellular space by cleavage removal of glutamic acid and then glycine to LTD 4 and LTE 4 , respectively. The type 1 cys-LT receptor (CysLT 1 R) is the high affinity receptor for LTD 4 , whereas the type 2 receptor (CysLT 2 R) can bind both LTC 4 and LTD 4 with one-log less affinity than that of CysLT 1 R for LTD 4 in transfected cells (3, 4). The cys-LTs are mediators of bronchial asthma on the basis of their potent bronchoconstrictive activity via the CysLT 1 R in pharmacologic studies and the clinical effectiveness of CysLT 1 R antagonists (5, 6).LTE 4 , the most abundant cys-LT at sites of inflammation due to its stab...

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“…LTD 4 binds CysLT 1 with higher affinity than LTC 4 , whereas CysLT 2 binds these cysLTs with equal affinity. LTE 4 has only weak activity on either CysLT 1 (23,24) or CysLT 2 (25,26) and has therefore been generally considered to be a stable inactive breakdown product, although there is accumulating evidence that LTE 4 can stimulate inflammatory responses through mechanisms independent of CysLT 1 or CysLT 2 (27)(28)(29)(30)(31) CysLT 1 mediates bronchoconstriction and also a range of proinflammatory effects including activation and migration of leukocytes (21,32,33), whereas CysLT 2 may mediate the vasoactive effects of LTC 4 and LTD 4 . The leukotriene antagonists approved for use in asthma and allergic rhinitis, most notably montelukast, block the action of cysLTs (predominantly LTD 4 ) on CysLT 1 but do not inhibit CysLT 2 -mediated effects.…”

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confidence: 99%

Leukotriene E4 Activates Human Th2 Cells for Exaggerated Proinflammatory Cytokine Production in Response to Prostaglandin D2

Xue

Barrow

Fleming

et al. 2012

The Journal of Immunology

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PGD2 exerts a number of pro-inflammatory responses through a high affinity interaction with chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) and has been detected at high concentrations at sites of allergic inflammation. Since cysteinyl leukotrienes (cysLTs) are also produced during the allergic response we investigated the possibility that cysLTs may modulate the response of human Th2 cells to PGD2. PGD2 induced concentration-dependent Th2 cytokine production in the absence of TCR stimulation. Leukotrienes D4 (LTD4) and E4 (LTE4) also stimulated the cytokine production but were much less active than PGD2. However, when combined with PGD2, cysLTs caused a greater than additive enhancement of the response, with LTE4 being most effective in activating Th2 cells. LTE4 enhanced calcium mobilisation in response to PGD2 in Th2 cells without affecting endogenous PGD2 production or CRTH2 receptor expression. The effect of LTE4 was inhibited by montelukast but not by the P2Y12 antagonistmethylthioadenosine 5′-monophosphate. The enhancing effect was also evident with endogenous cysLTs produced from immunologically activated mast cells since inhibition of cysLT action by montelukast or cysLT sythesis by MK886, an inhibitor of 5-LO-activating protein, reduced the response of Th2 cells to the levels produced by PGD2 alone. These findings reveal that cysLTs, in particular LTE4, have a significant pro-inflammatory impact on T cells and demonstrate their effects on Th2 cells are mediated by a montelukast-sensitive receptor.

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The leukotriene E4 puzzle: Finding the missing pieces and revealing the pathobiologic implications

Cited by 94 publications

References 41 publications

Leukotriene C4 prevents the complete maturation of murine dendritic cells and modifies interleukin-12/interleukin-23 balance

Leukotriene C4 prevents the complete maturation of murine dendritic cells and modifies interleukin-12/interleukin-23 balance

Identification of GPR99 Protein as a Potential Third Cysteinyl Leukotriene Receptor with a Preference for Leukotriene E4 Ligand

Leukotriene E4 Activates Human Th2 Cells for Exaggerated Proinflammatory Cytokine Production in Response to Prostaglandin D2

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