Specific inhibition of leukotriene B4 (LTB4)‐induced neutrophil emigration by 20‐hydroxy LTB4: implications for the regulation of inflammatory responses

Pettipher, E. R.; Salter, E. D.; Breslow, R; Raycroft, Loretta; Showell, Henry J.

doi:10.1111/j.1476-5381.1993.tb13827.x

Cited by 35 publications

(26 citation statements)

References 37 publications

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“…The major pathway for the catabolism and inactivation of LTB 4 in human neutrophils involves microsomal -hydroxylation by CYP4F3 (11). This reaction generates 20-OH LTB 4 , which can further inhibit LTB 4 activities by down-regulating BLT1 (23). The ability of LTB 4 to amplify an inflammatory response is, therefore, counterbalanced by the expression of CYP4F3.…”

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confidence: 99%

Myeloid Expression of Cytochrome P450 4F3 Is Determined by a Lineage-specific Alternative Promoter

Christmas¹,

Carlesso

Shang³

et al. 2003

Journal of Biological Chemistry

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The cytochrome P450 4F3 (CYP4F3) gene encodes two functionally distinct enzymes that differ only by the selection of exon 4 (CYP4F3A) or exon 3 (CYP4F3B). CYP4F3A inactivates leukotriene B 4 , a reaction that has significance for controlling inflammation. CYP4F3B converts arachidonic acid to 20-hydroxyeicosatetraenoic acid, a potent activator of protein kinase C. We have previously shown that mRNAs coding for CYP4F3A and CYP4F3B are generated from distinct transcription start sites in neutrophils and liver. We therefore investigated mechanisms that regulate the cell-specific expression of these two isoforms. Initially, we analyzed the distribution of CYP4F3 in human leukocytes and determined a lineage-specific pattern of isoform expression. CYP4F3A is expressed in myeloid cells and is coordinate with myeloid differentiation markers such as CD11b and myeloperoxidase during development in the bone marrow. In contrast, CYP4F3B expression is restricted to a small population of CD3؉ T lymphocytes. We identified distinct transcriptional features in myeloid, lymphoid, and hepatic cells that indicate the presence of multiple promoters in the CYP4F3 gene. The hepatic promoter depends on a cluster of hepatocyte nuclear factor sites 123-155 bp upstream of the initiator ATG codon. The myeloid promoter spans 400 bp in a region 468 -872 bp upstream of the ATG codon; it is associated with clusters of CACCT sites and can be activated by ZEB-2, a factor primarily characterized as a transcriptional repressor in cells that include lymphocytes. ZEB-2 interacts with C-terminal binding protein and Smads, and this would provide opportunities for integrating environmental signals in myelopoiesis and inflammation.The ability of cells to attain differentiated stages in development and to alter their functional phenotype in inflammatory settings depends on lineage-specific and cytokine-dependent transcription factors that either activate or repress target genes. Distinct patterns of transcription factors are associated with the myeloid and lymphoid lineages in hematopoiesis (1) and with the induction of pro-inflammatory genes in host defense (2). Transcription factor activity is context-dependent; a repressor of one gene can activate a different gene associated with an opposing function or alternative cell lineage (3). This has implications for the coordinated induction and repression of sets of genes that are functionally related. ZEB-1 (␦EF1, Zfhx1a) and ZEB-2 (SIP1, Zfhx1b) are recently characterized two-handed zinc finger transcription factors (4, 5) that may function as both gene silencers and activators. ZEBs repress transcription of genes that include IL-2, CD4, and GATA-3 in lymphocytes (6 -8), whereas their role in myeloid cells has not been determined. The C-terminal binding protein (CtBP) 1 is a corepressor for ZEBs and other factors but does not bind DNA directly (9). Recent evidence suggests that ZEBs can activate the vitamin D 3 receptor gene in colon carcinoma cells (10).Cytochrome P450 4F3 (CYP4F3) functions to control i...

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mentioning

confidence: 99%

Myeloid Expression of Cytochrome P450 4F3 Is Determined by a Lineage-specific Alternative Promoter

Christmas¹,

Carlesso

Shang³

et al. 2003

Journal of Biological Chemistry

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“…Both the peptidyl leukotrienes and LTB4 increase the adhesion of leukocytes to endothelial cells (2,6). LTB4 is also a potent chemotactic factor for neutrophils (7)(8)(9), and because it can also lessen the chemotactic capacity of neutrophils over time, LTB4 has been proposed to play a role in preventing migration of leukocytes away from sites of inflammation (10).…”

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confidence: 99%

Altered inflammatory responses in leukotriene-deficient mice.

Goulet

Snouwaert²,

Latour³

et al. 1994

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

176

130

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Leukotrienes have been implicated in the regulation of immune responses, including inflammation and immediate hypersensitivity reactions. Here, we describe the phenotypic analysis of leukotriene-deficient mice generated by inactivation of the 5-lipoxygenase (SLO) gene. These 5LO(-/-) mice were unable to synthesize detectable levels of leukotrienes and were more resistant to lethal anaphylaxis induced by platelet-activating factor. The intensity of an acute inflammatory response induced by arachidonic acid was similar in 5LO(-/-) mice and controls. However, the response in 5LO(-/-) mice, but not in controls, could be virtually eliminated by a cyclooxygenase inhibitor. These data suggest that inflammatory responses are modulated by arachidonic acid metabolites through a variety of interconnected mechanisms. This has important implications for understanding the early events of an inflammatory response and for designing drugs for use in therapeutic intervention.

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“…Known numbers of mouse neutrophils (harvested from the peritoneal cavity after injection of oyster glycogen) were included in each assay as a standard curve and data are expressed as numbers of neutrophil equivalents per site. Drug was dosed orally 1 hr prior to injection of LTB4 (9).…”

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confidence: 99%

Leukotriene B4 plays a critical role in the progression of collagen-induced arthritis.

Griffiths

Pettipher

Koch

et al. 1995

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

194

112

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Leukotriene B4 (LTB4) is a product of the 5-lipoxygenase pathway of arachidonic acid metabolism. LTB4 is a potent chemotactic factor for neutrophils and has been postulated to play an important role in a variety of pathological conditions including rheumatoid arthritis (RA), psoriasis, and inflammatory bowel disease. Rheumatoid arthritis (RA) is a chronic inflammatory polyarthritis that is inadequately treated with currently available drugs (1). One potential strategy to better treat this disease is to reduce the influx of leukocytes into the joint, since recent studies have shown that the extent of neutrophil infiltration into the joints of RA patients precedes clinical signs of inflammation and is predictive of pain (2). There are a number of mediators of the inflammatory response that could potentially be responsible for neutrophil accumulation, but leukotriene B4 (LTB4) is an attractive target since it is a potent chemotactic agent for human neutrophils (3), is produced in large amounts by these cells, and is found in the synovial fluid of patients with RA (4).In this paper, we describe experiments to assess the role of LTB4 in a murine model of RA, collagen-induced arthritis. The immunological and histological features of this model resemble those seen in RA patients. The strategy we employed was to use a LTB4 receptor antagonist to block the biological effects of endogenously produced LTB4. Several potent and selective LTB4 receptor antagonists, with a variety of structural types, have been reported (reviewed in ref. 5). However, there are no data on the efficacy of these agents in models of arthritis. CP-105,696, (+)-1-(3S,4R)-[3-(4-phenylbenzyl)-4-hydroxychroman-7-yl]cyclopentane carboxylic acid, is a newly discovered LTB4 receptor antagonist that has a high affinity OH for human and mouse LTB4 receptors and has a long plasma half-life in the mouse, which allows the maintenance of pharmacologically relevant concentrations of the drug with a once daily dosing protocol. Here we report the use of CP-105,696 to demonstrate the importance of LTB4 as a critical mediator in the pathogenesis of murine collagen-induced arthritis. MATERIALS AND METHODSIn Vitro LTB4 Receptor Ligand Binding Assays. The procedure for [3H]LTB4 binding was adapted from the method of Cheng and co-workers (6). Binding was performed in 150 ,ul in a buffer containing 50 mM Tris HCl (pH 7.3), 10 mM MgCl2, 9% methanol, 0.7 nM [3H]LTB4 (5920-7400 GBq/ mmol; New England Nuclear), and either 0.83 mg (murine spleen) or 0.13 mg (human neutrophil) of membrane per ml. Unlabeled LTB4 was added at a concentration of 5 ,uM to determine nonspecific binding. Incubations were carried out in microtiter plates at 4°C for 30 min and the bound ligand was separated from the free ligand with a Betaplate apparatus (Pharmacia LKB) with double-thickness glass fiber filter mats.In Vitro Chemotaxis Assay. Chemotaxis assays were performed as described by Harvath and co-workers (7). Neutrophils were isolated according to the procedure of Ferrante and Thong (8...

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Specific inhibition of leukotriene B₄ (LTB₄)‐induced neutrophil emigration by 20‐hydroxy LTB₄: implications for the regulation of inflammatory responses

Cited by 35 publications

References 37 publications

Myeloid Expression of Cytochrome P450 4F3 Is Determined by a Lineage-specific Alternative Promoter

Myeloid Expression of Cytochrome P450 4F3 Is Determined by a Lineage-specific Alternative Promoter

Altered inflammatory responses in leukotriene-deficient mice.

Leukotriene B4 plays a critical role in the progression of collagen-induced arthritis.

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