12(R)-hydroxy-5,8,10,14-eicosatetraenoic acid is a chemoattractant fo human polymorphonuclear leucocytes in vitro

Fm, Cunningham; Pm, Woollard

doi:10.1016/0090-6980(87)90264-4

Cited by 79 publications

(22 citation statements)

References 13 publications

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“…During psoriasis, 12-HETE is highly elevated, and 12(R)-HETE is the predominant form detected (Hammarstrom et al, 1975;Woollard, 1986). Neutrophil infiltration is a common characteristic of psoriasis, and topical application of 12(R)-HETE produces erythema and neutrophil accumulation (Cunningham and Woollard, 1987). These results together support the conclusion that 12(R)-HETE may play a role during skin inflammation.…”

Section: Discussionsupporting

confidence: 78%

12(R)-Hydroxy-5(Z),8(Z),10(E),14(Z)-eicosatetraenoic Acid [12(R)-HETE], an Arachidonic Acid Derivative, Is an Activator of the Aryl Hydrocarbon Receptor

Chiaro¹,

Patel²,

Perdew³

2008

Mol Pharmacol

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The aryl hydrocarbon receptor (AHR) is a ligand-regulated transcription factor that can be activated by structurally diverse chemicals, ranging from environmental carcinogens to dietary metabolites. Evidence supporting a necessary role for the AHR in normal biology has been established; however, identification of key endogenous ligand/activator remains to be established. Here, we report the ability of 12(R)-hydroxy-5(Z),8(Z),10(E), 14(Z)-eicosatetraenoic acid [12(R)-HETE], an arachidonic acid metabolite produced by either a lipoxygenase or cytochrome P-450 pathway, to act as a potent indirect modulator of the AHR pathway. In contrast, structurally similar HETE isomers failed to demonstrate significant activation of the AHR. Electrophoretic mobility shift assays, together with ligand competition binding experiments, have demonstrated the inability of 12(R)-HETE to directly bind or directly activate the AHR to a DNA binding species in vitro. However, cell-based xenobioticresponsive element-driven luciferase reporter assays indicate the ability of 12(R)-HETE to modulate AHR activity, and quantitation of induction of an AHR target gene confirmed 12(R)-HETE's ability to activate AHR-mediated transcription, even at high nanomolar concentrations in human hepatoma (HepG2)-and keratinocyte (HaCaT)-derived cell lines. One explanation for these results is that a metabolite of 12(R)-HETE is acting as a direct ligand for the AHR. However, several known metabolites failed to exhibit AHR activity. The ability of 12(R)-HETE to activate AHR target genes required receptor expression. These results indicate that 12(R)-HETE can serve as a potent activator of AHR activity and suggest that in normal and inflammatory disease conditions in skin, 12(R)-HETE is produced, perhaps leading to AHR activation.

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Section: Discussionsupporting

confidence: 78%

12(R)-Hydroxy-5(Z),8(Z),10(E),14(Z)-eicosatetraenoic Acid [12(R)-HETE], an Arachidonic Acid Derivative, Is an Activator of the Aryl Hydrocarbon Receptor

Chiaro¹,

Patel²,

Perdew³

2008

Mol Pharmacol

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“…The recent identification of 12(R)-HETE as the major stereoisomer of 12-HETE present in lesional psoriatic scale (Woollard, 1986) and the chemoattractant activity of this monohydroxy fatty acid for human neutrophils in vitro Cunningham & Woollard, 1987;Evans et al, 1987), promoted the present investigation of the chemotactic activity of 12(R)-HETE for human lymphocytes, since neutrophilic and lymphocytic infiltrates are characteristic histological features of psoriasis.…”

Section: Methodsmentioning

confidence: 99%

“…The monohydroxy metabolite of arachidonic acid, 8,10,, has been found in elevated levels in samples from lesional psoriatic skin, when compared to those from normal skin (Hammarstrom et al, 1975;Camp et al, 1983) and stereochemical analysis of psoriatic scale-derived 12-HETE has shown that the major stereoisomer present is 12(R)HETE (Woollard, 1986). Analysis of the biological activity of 12(R)-HETE has shown it to be a more potent chemokinetic agent for human neutrophils in vitro than the platelet product, 12(S)-HETE , Cunningham & Woollard, 1987Evans et al, 1987).…”

Section: Introductionmentioning

confidence: 99%

Contrasting in vitro lymphocyte chemotactic activity of the hydroxyl enantiomers of 12‐hydroxy‐5,8,10,14‐eicosatetraenoic acid

Bacon

Camp

Cunningham

et al. 1988

British J Pharmacology

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The chemotactic activity of 12(R)‐hydroxy‐5,8,10,14‐eicosatetraenoic acid (12(R)‐HETE), 12(S)‐HETE and leukotriene B4 (LTB4) for human mixed peripheral blood lymphocytes has been assessed in a 48‐well microchemotaxis assay. Responses to the standard lymphocyte chemoattractants, zymosan‐activated plasma, casein and N‐formyl‐methionyl‐leucyl‐phenylalanine (fMLP) were also measured. 12(R)‐HETE was shown to be chemotactic for lymphocytes over the range 5 × 10−7 to 5 × 10−5 m. In contrast, negligible chemotactic responses to 12(S)‐HETE were obtained. LTB4 was 200 times more potent than 12(R)‐HETE as a lymphocyte chemoattractant, although maximal responses to the two agonists were similar. 12(R)‐HETE and LTB4, which are present in extracts of samples from the skin lesions of psoriasis, may be, at least in part, responsible for the lymphocyte infiltrate which is a characteristic feature of this disease.

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“…These mediators are characterized by their ability to chemoattract and activate polymorphonuclear leukocytes (PMNs), suggesting that an important function of epithelial cells is to initiate the mucosal influx of PMNs. The arachidonic acid metabolites leukotriene B 4 (LTB 4 ), 12-hydroxyeicosatetraenoic acid (12-HETE), and 15-HETE regulate PMN functions, including chemotaxis (6,17,33,42), degranulation (13,38,41), and adherence (7), which may indicate the critical role of these metabolites for early events in inflammation.…”

mentioning

confidence: 99%

Bacterial Challenge Stimulates Formation of Arachidonic Acid Metabolites by Human Keratinocytes and Neutrophils In Vitro

Eberhard

Jepsen

Pohl

et al. 2002

Clin Vaccine Immunol

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Although the interactions of bacteria with keratinocytes induce the synthesis of various mediators, the capability of epithelial cells to form arachidonic acid mediators has not been studied, and therefore the first part of this study was initiated. The complex mixture of epithelium-derived mediators suggests that chemoattraction is not their only effect on neutrophils and that they may also affect neutrophil mediator synthesis. The effect of epithelium-derived mediators on neutrophil eicosanoide synthesis was evaluated in the second part of this study. We incubated human keratinocytes with human-pathogenic bacteria for 2 h and harvested the supernatants after 4, 6, 10, and 18 h of culture. Subsequently, the supernatants were coincubated for 5 min with human neutrophils with or without arachidonic acid. The formation of the arachidonic acid metabolites prostaglandin E 2 (PGE 2 ), leukotriene B 4 (LTB 4 ), 12-hydroxyeicosatetraenoic acid (12-HETE), and 15-HETE in keratinocytes and neutrophils was measured by reverse-phase high-pressure liquid chromatography. We demonstrated for the first time that keratinocytes produced significant amounts of LTB 4 and 12-HETE 4 to 6 h after bacterial challenge. Upon stimulation with epithelial supernatants, neutrophils produced significant amounts of PGE 2 , LTB 4 , 12-HETE, and 15-HETE throughout the observation period of 18 h, with a maximum synthesis by supernatants harvested 4 to 10 h after bacterial infection. The results of the study suggest that arachidonic acid mediator formation by epithelial cells following bacterial challenge may act as an early inflammatory signal for the initiation of the immune response. The epithelial supernatants were capable of inducing the formation of arachidonic acid mediators by neutrophils, which may have further regulatory effects on the immune response.Although the mechanisms controlling inflammation are poorly understood, the release of pro-and anti-inflammatory mediators plays a central role in the initiation, perpetuation, and limitation of this process. Bacterial infection is an important stimulus for the synthesis of inflammatory mediators in human tissues. Epithelial cells are the first cell line that interacts with bacteria and causes the increased expression and secretion of a number of cytokines and proinflammatory mediators (24). These mediators are characterized by their ability to chemoattract and activate polymorphonuclear leukocytes (PMNs), suggesting that an important function of epithelial cells is to initiate the mucosal influx of PMNs. The arachidonic acid metabolites leukotriene B 4 (LTB 4 ), 12-hydroxyeicosatetraenoic acid (12-HETE), and 15-HETE regulate PMN functions, including chemotaxis (6, 17, 33, 42), degranulation (13,38,41), and adherence (7), which may indicate the critical role of these metabolites for early events in inflammation.The synthesis of various inflammatory mediators by keratinocytes upon bacterial infection suggests that the induction of chemokinesis is not the only functional change that is induce...

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12(R)-hydroxy-5,8,10,14-eicosatetraenoic acid is a chemoattractant fo human polymorphonuclear leucocytes in vitro

Cited by 79 publications

References 13 publications

12(R)-Hydroxy-5(Z),8(Z),10(E),14(Z)-eicosatetraenoic Acid [12(R)-HETE], an Arachidonic Acid Derivative, Is an Activator of the Aryl Hydrocarbon Receptor

12(R)-Hydroxy-5(Z),8(Z),10(E),14(Z)-eicosatetraenoic Acid [12(R)-HETE], an Arachidonic Acid Derivative, Is an Activator of the Aryl Hydrocarbon Receptor

Contrasting in vitro lymphocyte chemotactic activity of the hydroxyl enantiomers of 12‐hydroxy‐5,8,10,14‐eicosatetraenoic acid

Bacterial Challenge Stimulates Formation of Arachidonic Acid Metabolites by Human Keratinocytes and Neutrophils In Vitro

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