Dermis-Derived 15-Hydroxy-eicosatertraenoic Acid Inhibits Epidermal 12-Lipoxygenase Activity

Kragballe, Knud; Pinnamaneni, Gayatri; Desjarlais, L.; Duell, Elizabeth A.; Voorhees, John J.

doi:10.1111/1523-1747.ep12455564

Cited by 55 publications

(17 citation statements)

References 19 publications

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“…This comparison showed that IL-8 and epithelial supernatants were not as effective in LTB 4 stimulation as A23187 and suggests additional regulatory capacities of IL-8 or epithelial supernatants for the 5-lipoxygenase pathway. This proposed additional regulation of cyclooxygenase and lipoxygenase pathways could be of epithelial origin or by the paracrine action of neutrophil derived arachidonic acid mediators itself (7,14,19,26,43,44).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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 hav ing a similar action profile the involvement in the course of the disease showed some differ ences: LTB4 was found in acute psoriatic lesions, 12-R-HETE predominantly in chronic plaque lesions [11], The source of mediators seemed different, 12-R-HETE most likely to be formed in the epidermal kératinocyte [12] and LTB4 to be produced by the neutrophil [13], In contrast to 12-HETE and LTB4, 15-HETE seemed to counteract the disturbances in the arachidonic acid metabolism and was thought to have a protective role against psoriasis. In vitro, 15-HETE inhibited the 5 -and 12-lipoxygenase enzymes and the LTB4-induced chemotaxis [14][15][16]. In vivo, 15-HETE had no inflammatory or hyperproliferative proper ties [17].…”

Section: -5]mentioning

confidence: 99%

Testing of Lipoxygenase Inhibitors, Cyclooxygenase Inhibitors, Drugs with Immunomodulating Properties and Some Reference Antipsoriatic Drugs in the Modified Mouse Tail Test, an Animal Model of Psoriasis

Bosman

1994

Skin Pharmacol Physiol

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Topical administration of lipoxygenase and cyclooxygenase inhibitors, antipsoriatic drugs and some immunomodulating drugs on adult mouse tail scales showed variable induction of of orthokeratosis. Dithranol and retinoic acid showed ED₅₀ concentrations of 0.5% and 0.23%, respectively. The lipoxygenase inhibitors catechol and octyl gallate showed ED₅₀ of 2.5 and 13.4%. 10% lonapalene showed 20% activity, curcumin, linoleic acid, primrose oil and AA673 10–15% activity, methyl and ethyl gallate 5% activity, nordihydroguaiaretic acid, diethylcarbamazine, ebselen, esculetin, quercetin, AA861, gallic acid, dodecyl gallate and 15-hydroxyeicosatetraenoic acid no activity. The cyclooxygenase inhibitors indomethacin, acetylsalicylic acid and bufexamac were inactive, benoxaprof-en showed 14% activity. The immunomodulating drugs fluo-rouracil and triamcinolone showed > 10% activity, cyclosporin A and thalidomide no activity. Fumaric acid showed 5% activity. The results show that this model could be proposed for screening antipsoriatic drugs.

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“…The formation of LTB4 and 12-HETE is inhibited by 26], Uninvolved psoriatic dermis has a decreased capacity to form 15-HETE in vitro [27], which may be of importance for the development of psoriasis. Intralesional injections of 0.1 ml 10~5 M 15-HETE ad ministered once a week caused almost com pletely clearing of the injected psoriatic areas within 3 weeks of treatment [10].…”

Section: Discussionmentioning

confidence: 96%

15-Hydroxyeicosatetraenoic Acid (15-HETE) Specifically Inhibits LTB<sub>4</sub>-Induced Chemotaxis of Human Neutrophils

Ternowitz

Fogh

Kragballe³

1988

Skin Pharmacol Physiol

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15-Hydroxyeicosatetraenoic acid (15-HETE), a 15-lipoxygenase (15-LO) product of arachidonic acid has the potential to inhibit leukotriene formation. In the present study the effect of 15-HETE on leukotriene B₄ (LTB₄)-induced polymorphonuclear leukocytes (PMN) and monocyte chemotaxis was investigated. LTB₄-induced chemotaxis of PMNs was inhibited in a dose-dependent manner by 15-HETE. Maximum inhibition (68%) occurred at a 15-HETE concentration of 10^-4M. The 15-LO product of eicosapentaenoic acid (15-HEPE) was approximately 10 times less potent in inhibiting LTB₄-induced PMN chemotaxis. LTB₄-induced chemotaxis of monocytes was unaffected by both 15-HETE and 15-HEPE. Using N-formyl-methionyl-leucyl-phenylalanine (FMLP) and complement split product C5a as chemoattractants, 15-HETE did not decrease PMN chemotaxis. Furthermore, 15-HETE itself did not affect random migration of leukocytes. The present results demonstrate that 15-HETE inhibits LTB₄-induced chemotaxis of PMNs in vitro in a specific and selective way. Because 15-HETE not only inhibits formation, but also the effect of LTB₄, it may be important in regulating LTB₄-induced inflammation.

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Dermis-Derived 15-Hydroxy-eicosatertraenoic Acid Inhibits Epidermal 12-Lipoxygenase Activity

Cited by 55 publications

References 19 publications

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

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

Testing of Lipoxygenase Inhibitors, Cyclooxygenase Inhibitors, Drugs with Immunomodulating Properties and Some Reference Antipsoriatic Drugs in the Modified Mouse Tail Test, an Animal Model of Psoriasis

15-Hydroxyeicosatetraenoic Acid (15-HETE) Specifically Inhibits LTB<sub>4</sub>-Induced Chemotaxis of Human Neutrophils

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