CysLT2 receptor-mediated AQP4 up-regulation is involved in ischemic-like injury through activation of ERK and p38 MAPK in rat astrocytes

Li, Qi; Fang, San‐Hua; Shi, Wenzhen; Huang, Xueqin; Zhang, Xia-Yan; Lu, Yun-Bi; Zhang, Weiping; Wei, Er-Qing

doi:10.1016/j.lfs.2010.10.025

Cited by 47 publications

(42 citation statements)

References 36 publications

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“…Last, the question whether LTD 4 signaled exclusively through CysLTR 1 or through CysLTR 1 and CysLTR 2 in DCs remains a subject for further investigation. In particular, because there is a considerable "overlap" between both signaling pathways in terms of ERK 1, 2, p38 MAPK, and NF-B/AP-1 activation [49][50][51] Admittedly, it appears counterintuitive to assume that LTC 4 , a molecule typically involved in Th2-mediated diseases such as asthma or allergies, would improve the Th1 skewing capacity of DCs. However, our observations are not without precedence.…”

Section: Discussionmentioning

confidence: 99%

Leukotriene C4 induces migration of human monocyte–derived dendritic cells without loss of immunostimulatory function

Dannull

Schneider

Lee

et al. 2012

Blood

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Generation of human monocyte–derived dendritic cells (DCs) for cancer vaccination involves ex vivo maturation in the presence of proinflammatory cytokines and prostaglandin E(2) (PGE2). Although the inclusion of PGE2 during maturation is imperative for the induction of DC migration, PGE2 has unfavorable effects on the immunostimulatory capacity of these cells. Like PGE2, leukotrienes (LTs) are potent mediators of DC migration. We therefore sought to characterize the migratory and immunologic properties of DCs that matured in the presence of LTB4, LTC4, LTD4, and PGE2. Here, we demonstrate that DCs matured in the presence of LTC4, but not LTB4 or LTD4, are superior to PGE2-matured DCs in stimulating CD4+ T-cell responses and in inducing antigen-specific cytotoxic T lymphocytes (CTLs) in vitro without concomitant induction or recruitment of regulatory T cells (Tregs). LTC4-matured DCs migrate efficiently through layers of extracellular matrix and secrete higher levels of immunostimulatory IL-12p70 while producing reduced levels of immune-inhibitory IL-10, IL12p40, indoleamine-2,3-dioxidase, and TIMP-1 (tissue inhibitor of matrix metalloproteinases). Intracellular calcium mobilization and receptor antagonist studies reveal that, in contrast to LTD4, LTC4 did not signal through CysLTR1 in DCs. Collectively, our data suggest that LTC4 represents a promising candidate to replace PGE2 in DC maturation protocols for cancer vaccination.

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Section: Discussionmentioning

confidence: 99%

Leukotriene C4 induces migration of human monocyte–derived dendritic cells without loss of immunostimulatory function

Dannull

Schneider

Lee

et al. 2012

Blood

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“…Total RNA extraction and cDNA synthesis were performed as reported previously [30,31] . PCR was done on an Eppendorf Mastercy- The reactions were initially heated at 94°C for 1 min;…”

Section: Identification Of Aqp4 Deficiency Aqp4 Expressionmentioning

confidence: 99%

Aggravated inflammation and increased expression of cysteinyl leukotriene receptors in the brain after focal cerebral ischemia in AQP4-deficient mice

Shi

Zhao

et al. 2012

Neurosci. Bull.

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Objective Aquaporin-4 (AQP4), the main water channel protein in the brain, plays a critical role in water homeostasis and brain edema. Here, we investigated its role in the inflammatory responses after focal cerebral ischemia. MethodsIn AQP4-knockout (KO) and wild-type mice, focal cerebral ischemia was induced by 30 min of middle cerebral arterial occlusion (MCAO). Ischemic neuronal injury and cellular inflammatory responses, as well as the expression and localization of cysteinyl leukotriene CysLT 2 and CysLT 1 receptors, were determined at 24 and 72 h after MCAO.Results AQP4-KO mice showed more neuronal loss, more severe microglial activation and neutrophil infiltration, but less astrocyte proliferation in the brain after MCAO than wild-type mice. In addition, the protein levels of both CysLT 1 and CysLT 2 receptors were up-regulated in the ischemic brain, and the up-regulation was more pronounced in AQP4-KO mice. The CysLT 1 and CysLT 2 receptors were primarily localized in neurons, microglia and neutrophils; those localized in microglia and neutrophils were enhanced in AQP4-KO mice. Conclusion AQP4 may play an inhibitory role in postischemic inflammation.

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“…19,20 CysLT 2 R can mediate vascular permeability, 12,21 susceptibility to gastrointestinal tract inflammation, 22 and increased vulnerability to ischemic injury in the heart 11 and brain. 16,23 CysLT 2 R expression is increased after hypoxic/ ischemic stress. 11,[23][24][25] Previous work from our laboratory has shown that CysLT 2 R-selective antagonism can abrogate myocardial ischemia/reperfusion injury in transgenic mice overexpressing the human CysLT 2 R receptor in vascular endothelium (hEC-CysLT 2 R).…”

mentioning

confidence: 97%

“…9 CysLT 2 R research had been previously hampered by a lack of selective pharmacological agents, 10 the majority of work instead using the nonselective cysLT antagonist/partial agonist 11 or genetic models of CysLT 2 R expression modulation. 11,12 However, recent studies have characterized 2 novel CysLT 2 R-selective antagonists: HAMI3379 13 and BayCysLT 2 , [14][15][16] which are proving to be useful as tools in eicosanoid research.There is evidence linking cysLTs to cardiovascular disease and inflammation. Expression of components of the leukotriene synthesis pathway is found in human atherosclerotic lesions.…”

mentioning

confidence: 99%

Multiple-Site Activation of the Cysteinyl Leukotriene Receptor 2 Is Required for Exacerbation of Ischemia/Reperfusion Injury

Ballantyne

Mewburn

et al. 2014

ATVB

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Leukotrienes are potent proinflammatory lipid mediators synthesized from arachidonic acid via the actions of 5-lipoxygenase and 5-lipoxygenase-activating protein.Cysteinyl leukotrienes (cysLTs) are a subfamily of leukotriene molecules, thus termed because of a common cysteine moiety in their respective structures. The cysLTs, leukotriene C 4 , D 4 , and E 4 (LTC 4 , D 4 , and E 4 , respectively), exert their effects by binding to sequenced G-protein-coupled receptors: cysteinyl leukotriene receptor 1 (CysLT 1 R), cysteinyl leukotriene receptor 2 (CysLT 2 R), and a novel CysLT E receptor (GPR99).3 CysLT 1 R binds LTD 4 preferentially to LTC 4 , whereas CysLT 2 R binds LTD 4 and LTC 4 with equal affinity. Both receptors bind LTE 4 , the most stable and abundant cysLT, with weak affinity. 4 In contrast, GPR99 displays preferential binding affinity for LTE 4 , with weak affinity for LTC 4 and LTD 4 . Objective-Transgenic overexpression of the human cysteinyl leukotriene receptor 2 (CysLT 2 R) in murine endothelium exacerbates vascular permeability and ischemia/reperfusion injury. Here, we explore the underlying mechanisms of CysLT 2 R activation-mediated inflammation and delineate the relative contributions of endogenous murine CysLT 2 R and the transgene-derived receptor. Approach and Results-We created a novel mouse with only endothelial-expressed CysLT 2 R (endothelium-targeted overexpression mice [EC]/CysLT 2 R-knockout mice [KO]) by crossing EC with KO to dissect the role of endothelial CysLT 2 R in tissue injury. Surprisingly, we discovered that damage in EC/KO mice was not elevated (24% versus 47% EC) after ischemia/reperfusion. We examined vascular permeability and leukocyte recruitment/rolling responses in the cremaster vasculature after cysteinyl leukotriene (cysLT) stimulation. Mice possessing transgenic endothelial CysLT 2 R overexpression, whether EC or EC/KO, when stimulated with cysLTs, exhibited vascular hyperpermeability, declining leukocyte flux, and a transient increase in slow-rolling leukocyte fraction. and coronary endothelial cells. 9 CysLT 2 R research had been previously hampered by a lack of selective pharmacological agents, 10 the majority of work instead using the nonselective cysLT antagonist/partial agonist 11 or genetic models of CysLT 2 R expression modulation. 11,12 However, recent studies have characterized 2 novel CysLT 2 R-selective antagonists: HAMI3379 13 and BayCysLT 2 , [14][15][16] which are proving to be useful as tools in eicosanoid research.There is evidence linking cysLTs to cardiovascular disease and inflammation. Expression of components of the leukotriene synthesis pathway is found in human atherosclerotic lesions.17 Furthermore, genetic polymorphisms in 5-lipoxygenase pathway genes have been correlated to increased myocardial infarction and stroke risk in some populations 18 but not all. 19,20 CysLT 2 R can mediate vascular permeability, 12,21 susceptibility to gastrointestinal tract inflammation, 22 and increased vulnerability to ischemic injury in the heart 11 a...

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CysLT2 receptor-mediated AQP4 up-regulation is involved in ischemic-like injury through activation of ERK and p38 MAPK in rat astrocytes

Cited by 47 publications

References 36 publications

Leukotriene C4 induces migration of human monocyte–derived dendritic cells without loss of immunostimulatory function

Leukotriene C4 induces migration of human monocyte–derived dendritic cells without loss of immunostimulatory function

Aggravated inflammation and increased expression of cysteinyl leukotriene receptors in the brain after focal cerebral ischemia in AQP4-deficient mice

Multiple-Site Activation of the Cysteinyl Leukotriene Receptor 2 Is Required for Exacerbation of Ischemia/Reperfusion Injury

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