Leukotriene B4 receptor BLT1 mediates early effector T cell recruitment

Tager, Andrew M.; Bromley, Shannon K.; Medoff, Benjamin D.; Islam, Saleem; Bercury, Scott D.; Friedrich, Erik B.; Carafone, Andrew D.; Gerszten, Robert E.; Luster, Andrew D.

doi:10.1038/ni970

Cited by 370 publications

(341 citation statements)

References 53 publications

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“…LTs induce leukocyte recruitment to an inflammatory site both by stimulating chemotaxis and by promoting firm adhesion to endothelial cells. LTB 4 has long been known to induce neutrophil migration in vivo and in vitro (37), and is now recognized to participate in the in vivo trafficking of CD4 and CD8 T lymphocytes (38). cysLTs participate in dendritic cell trafficking to sites of Ag stimulation (39) as well as to lymph nodes (40).…”

Section: Antimicrobial Effector Functions Of Ltsmentioning

confidence: 99%

Leukotrienes: Underappreciated Mediators of Innate Immune Responses

Peters‐Golden¹,

Canetti²,

Mancuso

et al. 2005

The Journal of Immunology

278

244

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Leukotrienes are bronchoconstrictor and vasoactive lipid mediators that are targets in the treatment of asthma. Although they are increasingly recognized to exert broad proinflammatory effects, their role in innate immune responses is less well appreciated. These molecules are indeed synthesized by resident and recruited leukocytes during infection. Acting via cell surface G protein-coupled receptors and subsequent intracellular signaling events, they enhance leukocyte accumulation, phagocyte capacity for microbial ingestion and killing, and generation of other proinflammatory mediators. Interestingly, a variety of acquired states of immunodeficiency, such as HIV infection and malnutrition, are characterized by a relative deficiency of leukotriene synthesis. The data reviewed herein point to leukotrienes as underappreciated yet highly relevant mediators of innate immunity.

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Section: Antimicrobial Effector Functions Of Ltsmentioning

confidence: 99%

Leukotrienes: Underappreciated Mediators of Innate Immune Responses

Peters‐Golden¹,

Canetti²,

Mancuso

et al. 2005

The Journal of Immunology

278

244

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“…LTB 4 acting through its receptors (BLT1) can cause chemotaxis, degranulation, adhesion and enhance the survival of neutrophils. Although BLT1 was long known to be a neutrophil chemoattractant receptor, recent studies identified BLT1 expression on macrophages [22], smooth muscle cells [23], endothelial cells [24], activated T-cells [25] and mast cells [26] considerably expanding the potential role of LTB 4 . Recent experiments from our laboratory demonstrated functional expression of BLT1 on both mature and immature dendritic cells and having a direct effect in the control of adaptive immune responses [27].…”

Section: Leukotriene B 4 and Its Receptorsmentioning

confidence: 99%

Role of leukotriene B4 receptors in rheumatoid arthritis

Mathis

Jala

Haribabu

2007

Autoimmunity Reviews

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The purpose of this review is to summarize the role that murine models of arthritis are playing in the understanding of human rheumatoid arthritis and how leukotriene B 4 (LTB 4 ) is emerging as an important target in this field. Both the collagen-induced arthritis (CIA) model and the K/BxN serum transfer arthritis model have contributed to outline the potential mechanisms involved in inflammatory arthritis. Indeed, the CIA model has contributed to the development of effective anti-TNF and anti-IL-1β based treatments for RA that are currently in the clinic. Many recent studies in mouse models have suggested a critical role for LTB 4 and its receptors in the development of inflammatory arthritis. Inhibitors of LTB 4 biosynthesis as well as LTB 4 receptors are protective in mouse models of RA and mice deficient in the LTB 4 biosynthetic enzymes or LTB 4 receptors are resistant to disease development suggesting several promising targets for RA in this pathway. KeywordsRheumatoid Arthritis; Leukotriene B4 receptors; arthritis mouse models; FLAP Take home message• Mouse models of RA have provided a great deal of information on the mechanisms involved in human RA and led to the development of effective therapies and are likely to uncover additional therapeutic opportunities • Chemoattractants and cytokines form important amplification loops for perpetual joint inflammation in RA • Inhibition of inflammatory cell recruitment to the rheumatoid synovium represents a potential target for RA treatment.• LTB 4 and its receptors play a critical role in the recruitment of leucocytes to the inflammatory sites. Mice lacking either the enzymes involved in LTB 4 biosynthesis or the LTB 4 receptors are completely protected from the development of RA.• Unraveling the mechanisms of LTB 4 /BLT1 and LTB 4 /BLT2 axis and structure/ function of BLT1 and BLT2 will provide important insights into identification of novel and dual antagonists for blocking their function.

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“…LT-Rs are expressed on multiple target cells, including leukocytes, smooth muscle cells, and ECs (1). Recent studies implicate the 5-LO pathway in cardiovascular disease (11)(12)(13)(14)(15)(16)(17).Considerable information is available on cysLT 1 -R, whereas little is known about cysLT 2 -R. We have used human umibilical vein (HUV)ECs as a model of vascular cells to study cysLT 2 -R activation by demonstrating that cysLTs exclusively signal through cysLT 2 -R in this cell type (18): In fact, HUVECs are the first primary cell type that selectively expresses cysLT 2 -R. In the study detailed below, we determined HUVEC gene signatures in response to LTD 4 and characterized the resulting phenotypes. LTD 4 responses were compared with those of the prototype vasoactive agonist thrombin, which, in HUVEC, acts through protease-activated receptor (PAR)-1 (19).…”

mentioning

confidence: 99%

Cysteinyl leukotriene 2 receptor and protease-activated receptor 1 activate strongly correlated early genes in human endothelial cells

Uzonyi

Lötzer

Jahn

et al. 2006

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

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Cysteinyl leukotrienes (cysLT), i.e., LTC4, LTD4, and LTE4, are lipid mediators derived from the 5-lipoxygenase pathway, and the cysLT receptors cysLT 1-R͞cysLT2-R mediate inflammatory tissue reactions. Although endothelial cells (ECs) predominantly express cysLT 2-Rs, their role in vascular biology remains to be fully understood. To delineate cysLT2-R actions, we stimulated human umbilical vein EC with LTD 4 and determined early induced genes. We also compared LTD4 effects with those induced by thrombin that binds to protease-activated receptor (PAR)-1. Stringent filters yielded 37 cysLT 2-R-and 34 PAR-1-up-regulated genes (>2.5-fold stimulation). Most LTD4-regulated genes were also induced by thrombin. Moreover, LTD4 plus thrombin augmented gene expression when compared with each agonist alone. Strongly induced genes were studied in detail: Early growth response (EGR) and nuclear receptor subfamily 4 group A transcription factors; E-selectin; CXC ligand 2; IL-8; a disintegrin-like and metalloprotease (reprolysin type) with thrombospondin type 1 motif 1 (ADAMTS1); Down syndrome critical region gene 1 (DSCR1); tissue factor (TF); and cyclooxygenase 2. Transcripts peaked at Ϸ60 min, were unaffected by a cysLT 1-R antagonist, and were superinduced by cycloheximide. The EC phenotype was markedly altered: LTD 4 induced de novo synthesis of EGR1 protein and EGR1 localized in the nucleus; LTD4 up-regulated IL-8 formation and secretion; and LTD4 raised TF protein and TF-dependent EC procoagulant activity. These data show that cysLT 2-R activation results in a proinflammatory EC phenotype. Because LTD 4 and thrombin are likely to be formed concomitantly in vivo, cysLT 2-R and PAR-1 may cooperate to augment vascular injury.cysteinyl leukotriene 2 receptor gene signature ͉ protease-activated receptor 1 gene signature ͉ vascular inflammation L eukotrienes (LTs), i.e., LTB 4 and the cysteinyl LTs (cysLT) LTC 4 , LTD 4 , and LTE 4 constitute a group of lipid mediators derived from the 5-lipoxygenase (5-LO) pathway (1, 2). LTs are either produced by leukocytes at sites of inflammation or formed through transcellular metabolism after uptake and metabolism of leukocyte-derived LTA 4 by downstream enzymes of the 5-LO pathway (LTA 4 hydrolase and LTC 4 synthase) in cells that normally do not express 5-LO, such as endothelial cells (ECs) (3, 4). LTs act through G protein-coupled surface receptors (GPCRs), i.e., the LTB 4 receptors and the cysLT receptors (LT-Rs) (cysLT 1 -R and cysLT 2 -R) (5-10). LT-Rs are expressed on multiple target cells, including leukocytes, smooth muscle cells, and ECs (1). Recent studies implicate the 5-LO pathway in cardiovascular disease (11)(12)(13)(14)(15)(16)(17).Considerable information is available on cysLT 1 -R, whereas little is known about cysLT 2 -R. We have used human umibilical vein (HUV)ECs as a model of vascular cells to study cysLT 2 -R activation by demonstrating that cysLTs exclusively signal through cysLT 2 -R in this cell type (18): In fact, HUVECs are the first primary cell type that s...

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Leukotriene B4 receptor BLT1 mediates early effector T cell recruitment

Cited by 370 publications

References 53 publications

Leukotrienes: Underappreciated Mediators of Innate Immune Responses

Leukotrienes: Underappreciated Mediators of Innate Immune Responses

Role of leukotriene B4 receptors in rheumatoid arthritis

Cysteinyl leukotriene 2 receptor and protease-activated receptor 1 activate strongly correlated early genes in human endothelial cells

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