An Aspirin-Triggered Lipoxin A4 Stable Analog Displays a Unique Topical Anti-Inflammatory Profile

Schottelius, Arndt; Giesen, Claudia; Asadullah, Khusru; Fierro, Iolanda M.; Colgan, Sean P.; Bauman, John G.; Guilford, William H.; Perez, Hector D.; Parkinson, John F.

doi:10.4049/jimmunol.169.12.7063

Cited by 96 publications

(97 citation statements)

References 44 publications

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“…8. The concentrations of this lipid mediator that were effective against LSP1 were similar to those that block neutrophil chemotaxis and trans-epithelial/endothelial migration (4,8). Thus, we have identified a "target"/site of action for lipoxins in human cells that may explain some of the physiological effects of this mediator.…”

Section: Discussionmentioning

confidence: 76%

A Stable Aspirin-Triggered Lipoxin A4 Analog Blocks Phosphorylation of Leukocyte-Specific Protein 1 in Human Neutrophils

Ohira

Bannenberg

Arita

et al. 2004

The Journal of Immunology

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Lipoxins and their aspirin-triggered 15-epimers are endogenous anti-inflammatory agents that block neutrophil chemotaxis in vitro and inhibit neutrophil influx in several models of acute inflammation. In this study, we examined the effects of 15-epi-16-(p-fluoro)-phenoxy-lipoxin A4 methyl ester, an aspirin-triggered lipoxin A4-stable analog (ATLa), on the protein phosphorylation pattern of human neutrophils. Neutrophils stimulated with the chemoattractant fMLP were found to exhibit intense phosphorylation of a 55-kDa protein that was blocked by ATLa (10–50 nM). This 55-kDa protein was identified as leukocyte-specific protein 1, a downstream component of the p38-MAPK cascade in neutrophils, by mass spectrometry, Western blotting, and immunoprecipitation experiments. ATLa (50 nM) also reduced phosphorylation/activation of several components of the p38-MAPK pathway in these cells (MAPK kinase 3/MAPK kinase 6, p38-MAPK, MAPK-activated protein kinase-2). These results indicate that ATLa exerts its anti-inflammatory effects, at least in part, by blocking activation of the p38-MAPK cascade in neutrophils, which is known to promote chemotaxis and other proinflammatory responses by these cells.

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Section: Discussionmentioning

confidence: 76%

A Stable Aspirin-Triggered Lipoxin A4 Analog Blocks Phosphorylation of Leukocyte-Specific Protein 1 in Human Neutrophils

Ohira

Bannenberg

Arita

et al. 2004

The Journal of Immunology

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“…Lipoxins and their 15-epimers, ATL, have proved to be highly effective in a range of experimental disease models, including renal ischemia-reperfusion injury (29), in skin diseases (39), and in gastritis (46). The stress-inducible enzyme HO-1 has also been shown to play important roles in the modulation of both innate and adaptative immunity.…”

Section: Discussionmentioning

confidence: 99%

Novel lipid mediator aspirin-triggered lipoxin A₄ induces heme oxygenase-1 in endothelial cells

Nascimento-Silva

Arruda

Barja‐Fidalgo

et al. 2005

American Journal of Physiology-Cell Physiology

102

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-Lipoxins (LX) and aspirintriggered LX (ATL) are eicosanoids generated during inflammation via transcellular biosynthetic routes that elicit distinct anti-inflammatory and proresolution bioactions, including inhibition of leukocytemediated injury, stimulation of macrophage clearance of apoptotic neutrophils, repression of proinflammatory cytokine production, and inhibition of cell proliferation and migration. Recently, it was reported that aspirin induces heme oxygenase-1 (HO-1) expression on endothelial cells (EC) in a COX-independent manner, what confers protection against prooxidant insults. However, the underlying mechanisms remain unclear. In this study, we investigated whether an aspirin-triggered lipoxin A4 stable analog, 15-epi-16-(para-fluoro)-phenoxy-lipoxin A4 (ATL-1) was able to induce endothelial HO-1. Western blot analysis showed that ATL-1 increased HO-1 protein expression associated with increased mRNA levels on EC in a timeand concentration-dependent fashion. This phenomenon appears to be mediated by the activation of the G protein-coupled LXA4 receptor because pertussis toxin and Boc-2, a receptor antagonist, significantly inhibited ATL-1-induced HO-1 expression. We demonstrate that treatment of EC with ATL-1 inhibited VCAM and E-selectin expression induced by TNF-␣ or IL-1␤. This inhibitory effect of the analog is modulated by HO-1 because it was blocked by SnPPIX, a competitive inhibitor that blocks HO-1 activity. Our results establish that ATL-1 induces HO-1 in human EC, revealing an undescribed mechanism for the anti-inflammatory activity of these lipid mediators. signaling transduction; resolution of inflammation LIPOXINS (LX) are endogenous lipid mediators that dampen the host response and orchestrate resolution of inflammation. In humans, three main biosynthetic pathways are described for LX formation, each involves transcellular biosynthetic use of intermediates between distinct cell types that are in close proximity during inflammatory responses (43). Monocytes, eosinophils, and airway-epithelial cells can convert arachidonate into 15S-hydroxyeicosatetraenoic acid (15S-HETE) by a 15-lipoxygenase (LO) catalyzed reaction. 15S-HETE is rapidly taken up by neutrophils and converted to lipoxin A 4 by a 5-LO-catalyzed reaction (43). The second pathway for lipoxin biosynthesis was determined for interactions that occur predominantly within the vasculature between 5-LO, present in myeloid cells, and 12-LO, which is present in platelets. The 5-LO product leukotriene A 4 is converted in a transcellular manner by platelet 12-LO to lipoxins (43). More recently, a third major pathway for lipoxin generation was discovered that involves aspirin and the action of cyclooxygenase (COX)-2 and 5-LO (11). Endothelial and epithelial cells express COX-2 in response to diverse stimuli such as cytokines, hypoxia, and bacterial infections. Aspirin acetylates COX-2 and switches its catalytic activity for conversion of arachidonic acid to 15R-HETE in lieu of prostanoid biosynthesis. 15R-HETE is released from endot...

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“…Statistical analysis. For all animal models, statistical analysis was performed with the ''modified Hemm'' (inhibition) test developed by Schering based on the program SAS SYSTEM FOR WINDOWS 6.12 (SAS Institute, Cary, NC) (18). Statistical significance in TAT, glucose induction, and ACTH suppression was assessed by using Dunnet's test.…”

Section: Methodsmentioning

confidence: 99%

“…Topical application of the nonspecific contact irritant croton oil, a mixture of several phorbol esters, leads to acute inflammation characterized by edema and a mainly granulocytic cell infiltration into the skin (17). Experiments were performed as recently described in detail (18). Briefly, for topical application, compounds were dissolved in the same vehicle as used for croton oil and were coapplied.…”

Section: Methodsmentioning

confidence: 99%

“…At the maximum of the inflammatory reaction, animals were killed, and ears (mice, area Ϸ1 cm 2 ) or a punch biopsy (rats, 10-mm diameter) were weighed as an indicator of edema formation, then snap-frozen in liquid nitrogen in polypropylene tubes and kept at -20°C for up to 24 h. Peroxidase activity assay. Peroxidase activity, as a measure for total granulocyte infiltration, was assayed by using a modification of a previously described method (19), as described by Schottelius et al (18). Induction of TAT in vivo.…”

Section: Methodsmentioning

confidence: 99%

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Dissociation of transactivation from transrepression by a selective glucocorticoid receptor agonist leads to separation of therapeutic effects from side effects

Schäcke¹,

Schottelius²,

Döcke³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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424

305

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Glucocorticoids (GCs) are the most commonly used antiinflammatory and immunosuppressive drugs. Their outstanding therapeutic effects, however, are often accompanied by severe and sometimes irreversible side effects. For this reason, one goal of research in the GC field is the development of new drugs, which show a reduced side-effect profile while maintaining the antiinflammatory and immunosuppressive properties of classical GCs. GCs affect gene expression by both transactivation and transrepression mechanisms. The antiinflammatory effects are mediated to a major extent via transrepression, while many side effects are due to transactivation. Our aim has been to identify ligands of the GC receptor (GR), which preferentially induce transrepression with little or no transactivating activity. Here we describe a nonsteroidal selective GR-agonist, ZK 216348, which shows a significant dissociation between transrepression and transactivation both in vitro and in vivo. In a murine model of skin inflammation, ZK 216348 showed antiinflammatory activity comparable to prednisolone for both systemic and topical application. A markedly superior sideeffect profile was found with regard to increases in blood glucose, spleen involution, and, to a lesser extent, skin atrophy; however, adrenocorticotropic hormone suppression was similar for both compounds. Based on these findings, ZK 216348 should have a lower risk, e.g., for induction of diabetes mellitus. The selective GR agonists therefore represent a promising previously undescribed class of drug candidates with an improved therapeutic index compared to classical GCs. Moreover, they are useful tool compounds for further investigating the mechanisms of GR-mediated effects.inflammation ͉ nuclear receptor ͉ dissociated glucocorticoid receptor ligand

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An Aspirin-Triggered Lipoxin A4 Stable Analog Displays a Unique Topical Anti-Inflammatory Profile

Abstract: Material

Cited by 96 publications

References 44 publications

A Stable Aspirin-Triggered Lipoxin A4 Analog Blocks Phosphorylation of Leukocyte-Specific Protein 1 in Human Neutrophils

A Stable Aspirin-Triggered Lipoxin A4 Analog Blocks Phosphorylation of Leukocyte-Specific Protein 1 in Human Neutrophils

Novel lipid mediator aspirin-triggered lipoxin A₄ induces heme oxygenase-1 in endothelial cells

Dissociation of transactivation from transrepression by a selective glucocorticoid receptor agonist leads to separation of therapeutic effects from side effects

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An Aspirin-Triggered Lipoxin A4 Stable Analog Displays a Unique Topical Anti-Inflammatory Profile

Abstract: Material

Cited by 96 publications

References 44 publications

A Stable Aspirin-Triggered Lipoxin A4 Analog Blocks Phosphorylation of Leukocyte-Specific Protein 1 in Human Neutrophils

A Stable Aspirin-Triggered Lipoxin A4 Analog Blocks Phosphorylation of Leukocyte-Specific Protein 1 in Human Neutrophils

Novel lipid mediator aspirin-triggered lipoxin A4 induces heme oxygenase-1 in endothelial cells

Dissociation of transactivation from transrepression by a selective glucocorticoid receptor agonist leads to separation of therapeutic effects from side effects

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Product

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Novel lipid mediator aspirin-triggered lipoxin A₄ induces heme oxygenase-1 in endothelial cells