Lipoxin A4 Stable Analogs Are Potent Mimetics That Stimulate Human Monocytes and THP-1 Cells via a G-protein-linked Lipoxin A4 Receptor

Abstract

Lipoxins display selective activities on human leukocytes that are either stimulatory or inhibitory, depending on the target cell type involved. In human PMN, LXA 4 induces chemokinesis but inhibits chemotaxis toward leukotriene B 4 (LTB 4 ) and N-formylmethionylleucylphenylalanine (FMLP) (7). LXA 4 also inhibits FMLP-induced PMN transmigration across intestinal epithelium (8). In addition, LTB 4 -and LTC 4 -induced PMN adherence to human umbilical vein endothelial cells (HUVEC) is reduced by ϳ70% by LXA 4 and LXB 4 (9) and aspirin-triggered 15-epi-LXA 4 also inhibits LTB 4 -stimulated PMN adherence to HUVEC at nanomolar concentrations and is ϳtwo times more potent than LXA 4 in this setting (6). LXA 4 and LXB 4 also down-regulate peptidoleukotriene-induced Pselectin expression on HUVEC (9). LXA 4 displays in vivo activity, with inhibition of PMN migration into the kidney in rat glomerulonephritis models (3) and inhibition of PMN diapedesis from postcapillary venules (10). In contrast to the downregulation of PMN, LX exhibit selective stimulatory activities in the monocyte, as we recently described potent activation of human monocyte migration and adherence to laminin by both LXA 4 and LXB 4 (11).Human monocytes were also found to rapidly convert more than 80% of added LXA 4 to novel metabolites via dehydrogenation and reduction of double bonds and the products were identified as 15-oxo-LXA 4

Eicosanoid Activation of Extracellular Signal-regulated Kinase1/2 in Human Epidermoid Carcinoma Cells

“…In eosinophils, leukotriene B 4 activates ERK1/2 but not JNK or p38 MAPK (63) and promotes hydrogen peroxide production in a PKC-dependent manner (64). Lipoxin A 4 increases intracellular calcium concentration in a manner inhibited by pertussis toxin (65). Leukotriene D 4 also increases calcium concentration in cells but by two pathways as follows: 1) by a pertussis toxin-sensitive pathway that results in the stimulation of extracellular calcium influx, and 2) by a pertussis toxin-insensitive pathway resulting in the mobilization of the intracellular calcium pool (45).…”

Targeting resolution of neuroinflammation after ischemic stroke with a lipoxin A4 analog: Protective mechanisms and long‐term effects on neurological recovery

“…LXA 4 binds with high affinity to the G‐protein‐coupled receptor ALX (also termed FPRL1/FPR2) (Chiang, Fierro, Gronert, & Serhan, 2000). ALX is expressed on many tissues and cells including neutrophils, monocytes, macrophages, endothelial cells, astrocytes, microglia, and neural stem cells (Koczulla et al., 2003; Maddox et al., 1997; Sodin‐Semrl, Spagnolo, Barbaro, Varga, & Fiore, 2004; Svensson, Zattoni, & Serhan, 2007; Wada et al., 2006). Depending on which cell type ALX is expressed, LXA 4 can have different effects.…”

“…Lipoxin A 4 bound to ALX on monocyte‐derived macrophages induces the nonphlogistic phagocytosis of apoptotic leukocytes, promoting resolution (Godson et al., 2000). In addition, LXA 4 via ALX triggers the chemotaxis and adherence to laminin of peripheral blood monocytes (Maddox & Serhan, 1996; Maddox et al., 1997). Since LXA 4 is rapidly inactivated in vivo , stable analogs have been synthesized (Chiang et al., 2000).…”

Lipoxin A4 Stimulates a Cytosolic Ca2+Increase in Human Bronchial Epithelium

“…Expression of the housekeeping gene hypoxanthine-guanine phosphoribosyltransferase was determined to provide an internal control for RT and PCR efficiencies. Peripheral blood mononuclear cells, from which the LXA 4 receptor has been cloned, were used as positive control (20). Representative electrophoretic analysis of the PCR products obtained is shown in Fig.…”

“…Intracellular Ca 2ϩ plays a central role in cellular functions including inflammatory processes, and interestingly LXA 4 stimulates a [Ca 2ϩ ] i increase in rainbow trout leukocytes (18), in human monocytes (19,20), and in human neutrophils (21 4 in airway epithelial cells, the description of the cellular mechanisms generating the response, and its consequence on ionic secretion.…”