Role of leukotriene B4 receptors in rheumatoid arthritis

Abstract

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.

Polymorphisms of COTL1 gene identified by proteomic approach and their association with autoimmune disorders

“…Rakonjac and coworkers reported that COTL1 up-regulates Ca 2+ -induced 5LO activity as a scaffold of 5LO in the absence of phosphatidylcholine by in vitro assays (Rakonjac et al, 2006). Mathis and co-workers demonstrated LTB 4 receptors play a critical role in the recruitment of leukocytes to the inflammatory sites in mouse model of RA (Mathis et al, 2007). Thus, our results suggest that up-regulation of COTL1 may affect the 5LO activity involved in LT biosynthesis, and mediate inflammation in RA.…”

12-hydroxyheptadecatrienoic acid promotes epidermal wound healing by accelerating keratinocyte migration via the BLT2 receptor

“…As such, LTB 4 plays crucial roles in inflammation and immune responses (Luster and Tager, 2004;Mathis et al, 2007). Two G protein-coupled receptors (GPCRs) for LTB 4 were originally cloned in our laboratory.…”

5-Lipoxygenase Metabolic Contributions to NSAID-Induced Organ Toxicity

“…Significant elevations of LTB 4 and LTC 4 from neutrophils are also present in animal models that mimic RA, suggesting that the 5-LOX pathway is significantly involved in generating inflammatory arthritis [148,149]. factors [152].…”

“…In patients with aspirin intolerance, nasal secretions contain increased levels of LTC 4 and LTD 4 histamine, and FLAP [55,56]. The incidence of aspirin-intolerant syndrome is about 10% of the US population, with most NSAIDs showing some level of cross-reactivity [57,58].…”

“…They are also intimately involved in allergic asthma, atopic dermatitis, allergic rhinitis, arthritis, atherosclerosis and ischemia, tumorigenesis, and septic shock [1][2][3][4][5][6][7]. LTs COX-1 and COX-2 could be accounted for due to compartmentalization within the cell.…”