Lipoxin and synthetic lipoxin analogs: an overview of anti-inflammatory functions and new concepts in immunomodulation

Abstract

Lipoxin A4 (LXA4) and lipoxin B4 (LXB4) were first identified in 1984 by Serhan and colleagues as 5- and 15-lipoxygenase interaction products of activated leukocytes. Endogenous transcellular biosynthesis of LXA4 and LXB4 occurs via interaction of leukocytes with epithelium, endothelium or platelets. Acetylation of cyclooxygenase-2 (COX-2) by aspirin can trigger 15-epi-LXA4 (ATL) biosynthesis. Elucidating the pharmacological actions of lipoxins and ATL was facilitated by total synthesis of LXA4 in 1988 by Nicolaou and colleagues. In 1994, Fiore and colleagues used [3H]-LXA4 to identify the cDNA for a human G-protein-coupled, high affinity LXA4 and ATL receptor (ALX-R/FPRL-1), providing the first hints for the molecular basis of lipoxin actions. The recognition that lipoxins and ATL undergo rapid, prostaglandin dehydrogenase (PGDH)-mediated metabolic inactivation led do the design and synthesis of first-generation PGDH-resistant LXA4, LXB4 and ATL analogs in 1995-1998 by Serhan, Petasis and colleagues. These relatively stable pharmacological agents, together with myeloid-specific ALX-R-expressing transgenic mice, have provided powerful tools to explore lipoxin functions in vivo. Here we briefly review the substantial body of evidence supporting the lipoxin --> ALX-R pathway as a novel and potent mechanism for preventing/resolving acute inflammation. Emphasis will also be placed on recent findings that lipoxins play new roles in "immunomodulation" via regulation of macrophage, dendritic cell, and T-lymphocyte effector functions in the setting of polarized T-helper cell responses (Th1 and Th2). These studies suggest roles for lipoxins as novel regulators of allergy and adaptive immunity and that lipoxins may have therapeutic potential in chronic immune disorders.