(from the application): Lipoxins (LX) are a unique class of eicosanoids containing conjugated tetraenes, which in nanogram quantities exhibit potent vascular and immunoregulatory activities (Serhan C.N. 1994. B.B.A. 1212: 1-25). Recently, we have characterized a myeloid cell-derived cDNA coding for a high affinity Lipoxin A4 (LXA4) receptor (LXA4R) that mediates LXA4 anti-inflammatory activities in PMN (Fiore et al, 1994. J. Exp. Med. 180: 253-60). In experiments in progress, we used the LXA4R full open reading frame cDNA as a probe to screen human umbilical vein endothelial cells (HUVEC) mRNA for the presence of a hybridizing signal. Messenger RNA derived from differentiated HL-60 cells served as positive control. A specific ~1.3 Kb signal was present in HUVEC. This band was clearly distinct from the 2.1 Kb band present in HL-60 cells. Screening of an HUVEC cDNA library, under way in our laboratory, has already identified a partial 5' encoding region of a cDNA with ~80% identity to the myeloid LXA4R. Because of the significance of LXA4 as a potential anti-inflammatory agent, we intend to clone, sequence and express the HUVEC-specific LXA4 receptor, and determine its biological relevance in the vascular pathophysiology of inflammatory events. These regulatory feedback mechanisms would be in agreement with recent in vivo results in a mouse leukotriene B4-induced inflammation model (Takano T., Fiore S., Maddox J.F., Brady H.R., Petasis N.A., and C.N. Serhan. J. Exp. Med., in press), where, after identifying the mouse homologue of the human LXA4R, we have shown that Lipoxins are as potent anti-inflammatory molecules as dexamethasone. Preliminary results also indicate that although """"""""naive"""""""" synovial fibroblasts do not express LXA4 or related receptors a specific mRNA signal for LXA4R is induced after cell-activation by IL-1beta. We hypothesize that induction of LXA4R might occur in other cell types and might serve to enact a negative-feedback regulation of pro-inflammatory modifications. Lipoxin A4-induced modifications endothelium cell adhesiveness, proliferation, cytokine generation and release will be specific objectives. LXA4 capacity to interact with the novel HUVEC receptor here characterized and the molecular mechanisms by which lipoxygenase mediators, and the set of cognate receptors, impact endothelial cells recruitment to the inflammatory processes, will clarify the contribution of these events to the pathophysiology of arthritides such as rheumatoid arthritis.
| Sodin-Semrl, S; Spagnolo, A; Barbaro, B et al. (2004) Lipoxin A4 counteracts synergistic activation of human fibroblast-like synoviocytes. Int J Immunopathol Pharmacol 17:15-25 |
| Sodin-Semrl, S; Taddeo, B; Tseng, D et al. (2000) Lipoxin A4 inhibits IL-1 beta-induced IL-6, IL-8, and matrix metalloproteinase-3 production in human synovial fibroblasts and enhances synthesis of tissue inhibitors of metalloproteinases. J Immunol 164:2660-6 |
| Kang, Y; Taddeo, B; Varai, G et al. (2000) Mutations of serine 236-237 and tyrosine 302 residues in the human lipoxin A4 receptor intracellular domains result in sustained signaling. Biochemistry 39:13551-7 |
