Lipoxin A4 elicits biological actions via at least two classes of receptors known to date: (1) ALXR on leukocytes and enlerocytes; and (2) a shared CysLT| subtype on endothelial and mesangial cells. ALXR belongs to the group of classical G protein-coupled receptors and was identified in both human and mouse and characterized using direct evidence including specific [3H]LXA4 binding and activation of functional responses with LXA4. In several tissues and cell types other than leukocytes, results of pharmacological experiments indicate that LXA4 acts via a subclass of peplido-leukolriene receptors (CysLT]) as a partial agonist. In addition, endothelial cells (HUVECs) exhibit specific [3H]LXA4 binding which can be inhibited by LTD4 and SKF104353 (CysLT, antagonist). The molecular origin of CysLT] is currently under investigation. ALXR is the first cloned lipoxygenase-derived eicosanoid receptor and. together with BLT. they are more akin to chemokine receptors than prostanoid receptors. The cytoplasmic signaling pathways and bioaclions of ALXR are cell type specific. In human PMNs. LXA4 stimulates rapid lipid remodeling with release of arachidonic acid in a pertussis toxin-sensitive fashion, and does not trigger significant increases in intracellular Ca"+ to serve as a second messenger. LXA4 inhibits PMN adhesion, chemotaxis. transmigration as well as degranulation and was implicated as endogenous 'stop signals' acting on PMNs. In human monocytes and THP-1 cells. LXA4 initiates intracellular Ca2+ release via ALXR but neither Ca2+ nor cAMP proved to be the required second messengers of lipoxin actions in these cell types, indicating different intracellular signaling pathways despite identical receptor cDNA sequences. LXA4 stimulates chemotaxis and adherence in monocytes but no other downstream responses of these cells, which may relate to the recruitment of monocytes to sites of wound healing and clearance. In agreement with in vitro results, ALXR agonists, namely LXA4, 15-epi-LXA4 (an aspirin-triggered LX) and their stable analogs, are topically active in inhibiting PMN infiltration as well as vascular permeability in murine skin inflammation. The development of these stable analogs will provide valuable tools to evaluate biological and pharmacological roles of ALXR as well as a novel means to develop selective therapies for inflammatory diseases. Since another eicosanoid. PGE2, couples to a variety of signal transduction pathways (i.e. generation of IP3 and [Са2+]4 as well as decrease or increase of cAMP) via distinct receptor subtypes and/or isoforms that are cell type and tissue specific (Negishi et al.9 1995), it is likely that given the range of LXA4 actions in vivo and its impact in isolated cell types, additional receptor systems will be identified.

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