Relationship between leukotriene B4 and immunological parameters in rheumatoid synovial fluids

Ahmadzadeh, N; Sato, Masao; Nobunaga, Masashi; Tawara, Tohru

doi:10.1007/bf00923346

Cited by 71 publications

(38 citation statements)

References 15 publications

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“…C5a and LTB 4 are elevated in the synovial fluid of patients with RA, and the activation level of the alternative complement pathway in the synovial fluid of patients with RA correlates with levels of LTB 4 (57). The concentration of C5a in RA synovial fluid averages ∼20 ng/mL (26,27), a concentration that we found induces the release of LTB 4 from mouse and human PMNs, suggesting that this pathway is relevant under physiological conditions.…”

Section: Discussionmentioning

confidence: 75%

Neutrophils orchestrate their own recruitment in murine arthritis through C5aR and FcγR signaling

Sadik

Kim

Iwakura

et al. 2012

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

126

112

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Neutrophil recruitment into the joint is a hallmark of inflammatory arthritides, including rheumatoid arthritis (RA). In a mouse model of autoantibody-induced inflammatory arthritis, neutrophils infiltrate the joint via multiple chemoattractant receptors, including the leukotriene B 4 (LTB 4 ) receptor BLT1 and the chemokine receptors CCR1 and CXCR2. Once in the joint, neutrophils perpetuate their own recruitment by releasing LTB 4 and IL-1β, presumably after activation by immune complexes deposited on joint structures. Two pathways by which immune complexes may activate neutrophils include complement fixation, resulting in the generation of C5a, and direct engagement of Fcγ receptors (FcγRs). Previous investigations showed that this model of autoantibody-induced arthritis requires the C5a receptor C5aR and FcγRs, but the simultaneous necessity for both pathways was not understood. Here we show that C5aR and FcγRs work in sequence to initiate and sustain neutrophil recruitment in vivo. Specifically, C5aR activation of neutrophils is required for LTB 4 release and early neutrophil recruitment into the joint, whereas FcγR engagement upon neutrophils induces IL-1β release and subsequent neutrophil-active chemokine production, ensuring continued inflammation. These findings support the concept that immune complex-mediated leukocyte activation is not composed of overlapping and redundant pathways, but that each element serves a distinct and critical function in vivo, culminating in tissue inflammation.

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Section: Discussionmentioning

confidence: 75%

Neutrophils orchestrate their own recruitment in murine arthritis through C5aR and FcγR signaling

Sadik

Kim

Iwakura

et al. 2012

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

126

112

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“…A role for LTB 4 in RA was suggested by several observations over the past two decades. LTB 4 levels in synovial fluids from patients with active RA were 5-fold higher relative to synovial fluids from osteoarthritis (15,16). Neutrophils from RA patients undergoing methotrexate therapy displayed both acute and chronic suppression of LTB 4 synthesis ex vivo (17).…”

Section: R Heumatoid Arthritis (Ra)mentioning

confidence: 97%

Targeted Disruption of Leukotriene B4 Receptors BLT1 and BLT2: A Critical Role for BLT1 in Collagen-Induced Arthritis in Mice

Shao

Prete

Bock

et al. 2006

The Journal of Immunology

100

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Leukotriene B4 mediates diverse inflammatory diseases through the G protein-coupled receptors BLT1 and BLT2. In this study, we developed mice deficient in BLT1 and BLT2 by simultaneous targeted disruption of these genes. The BLT1/BLT2 double-deficient mice developed normally and peritoneal exudate cells showed no detectable responses to leukotriene B4 confirming the deletion of the BLT1/BLT2 locus. In a model of collagen-induced arthritis on the C57BL/6 background, the BLT1/BLT2−/− as well as the previously described BLT1−/− animals showed complete protection from disease development. The disease severity correlated well with histopathology, including loss of joint architecture, inflammatory cell infiltration, fibrosis, pannus formation, and bone erosion in joints of BLT1/BLT2+/+ animals and a total absence of disease pathology in leukotriene receptor-deficient mice. Despite these differences, all immunized BLT1−/− and BLT1/BLT2−/− animals had similar serum levels of anti-collagen Abs relative to BLT1/BLT2+/+ animals. Thus, BLT1 may be a useful target for therapies directed at treating inflammation associated with arthritis.

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“…Although several hydroxyeicosatetraenoic acids were found to activate BLT2 (6), we recently identified 12(S)-hydroxyheptadeca-5Z, 8E, 10E-trienoic acid (12-HHT) as a very potent endogenous ligand for BLT2 (7). LTB 4 is produced in inf lammatory diseases such as psoriasis (8), bronchial asthma (9), ulcerative colitis (10), postischemic tissue injuries (11), and rheumatoid arthritis (12)(13)(14)(15).…”

mentioning

confidence: 99%

A distinctive role of the leukotriene B ₄ receptor BLT1 in osteoclastic activity during bone loss

Hikiji

Ishii

Yokomizo

et al. 2009

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

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Although leukotriene B4 (LTB4) is produced in various inflammatory diseases, its functions in bone metabolism remain unknown. Using mice deficient in the high-affinity LTB4 receptor BLT1, we evaluated the roles of BLT1 in the development of two bone resorption models, namely bone loss induced by ovariectomy and lipopolysaccharide. Through observations of bone mineral contents and bone morphometric parameters, we found that bone resorption in both models was significantly attenuated in BLT1-deficient mice. Furthermore, osteoclasts from BLT1-deficient mice showed reduced calcium resorption activities compared with wild-type osteoclasts. Osteoclasts expressed BLT1, but not the low-affinity LTB4 receptor BLT2, and produced LTB4. LTB4 changed the cell morphology of osteoclasts through the BLT1-Gi protein-Rac1 signaling pathway. Given the causal relationship between osteoclast morphology and osteoclastic activity, these findings suggest that autocrine/paracrine LTB4 increases the osteoclastic activity through the BLT1-Gi protein-Rac1 signaling pathway. Inhibition of BLT1 functions may represent a strategy for preventing bone resorption diseases.bone remodeling ͉ G protein-coupled receptor ͉ knockout mice ͉ lipid mediator ͉ osteoporosis ͉ L eukotriene B 4 (LTB 4 ), a metabolite of arachidonic acid, is a potent lipid mediator with various biological activities toward neutrophils and differentiated T cells, including chemotaxis, degranulation, and production of superoxide anions (1, 2). These actions of LTB 4 are mediated by specific cell surface receptors (BLTs). We previously cloned two distinct BLTs, BLT1 and BLT2 (3,4). BLT1 is a high-affinity receptor that mediates the inhibition of adenylate cyclase and calcium entry by coupling with the Gi-and Gq-classes of G proteins (5). BLT2 transduces comparable intracellular signals but has a lower affinity to LTB 4 (5). Although several hydroxyeicosatetraenoic acids were found to activate BLT2 (6), we recently identified 12(S)-hydroxyheptadeca-5Z, 8E, 10E-trienoic acid (12-HHT) as a very potent endogenous ligand for BLT2 (7). LTB 4 is produced in inf lammatory diseases such as psoriasis (8), bronchial asthma (9), ulcerative colitis (10), postischemic tissue injuries (11), and rheumatoid arthritis (12-15).Bone remodeling consists of old bone resorption by osteoclasts and new bone deposition by osteoblasts. Osteoclasts and osteoblasts participate in bone remodeling under the control of many hormones, cytokines (16,17), and autacoids, including lipid mediators (18). The effects of LTB 4 on bone resorption were investigated using organ cultures of mouse calvariae (19,20). LTB 4 enhanced calcium efflux from the mouse calvariae, suggesting that LTB 4 stimulates bone resorption (19). LTB 4 increased the formation of resorption pits by osteoclasts in rat bone tissues (20), suggesting that LTB 4 modulates bone resorption by increasing the number and/or activity of osteoclasts. However, few reports have provided definitive biochemical information about the mRNA/protein expression and ...

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Relationship between leukotriene B4 and immunological parameters in rheumatoid synovial fluids

Cited by 71 publications

References 15 publications

Neutrophils orchestrate their own recruitment in murine arthritis through C5aR and FcγR signaling

Neutrophils orchestrate their own recruitment in murine arthritis through C5aR and FcγR signaling

Targeted Disruption of Leukotriene B4 Receptors BLT1 and BLT2: A Critical Role for BLT1 in Collagen-Induced Arthritis in Mice

A distinctive role of the leukotriene B ₄ receptor BLT1 in osteoclastic activity during bone loss

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Relationship between leukotriene B4 and immunological parameters in rheumatoid synovial fluids

Cited by 71 publications

References 15 publications

Neutrophils orchestrate their own recruitment in murine arthritis through C5aR and FcγR signaling

Neutrophils orchestrate their own recruitment in murine arthritis through C5aR and FcγR signaling

Targeted Disruption of Leukotriene B4 Receptors BLT1 and BLT2: A Critical Role for BLT1 in Collagen-Induced Arthritis in Mice

A distinctive role of the leukotriene B 4 receptor BLT1 in osteoclastic activity during bone loss

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A distinctive role of the leukotriene B ₄ receptor BLT1 in osteoclastic activity during bone loss