Stimulation of protein kinase C redistribution and inhibition of leukotriene B4-induced inositol 1,4,5-trisphosphate generation in human neutrophils by lipoxin A4.

1. To test the hypothesis that protein kinase C (PKC) is involved in the inhibitory actions of lipoxin A4 (LXA4) on second messenger generation, we studied the effects of LXA4 on PKC in human neutrophils and on leukotriene B4 (LTB4)-stimulated inositol-1,4,5-trisphosphate (Ins(1,4,5)P3) generation. 2.

Effects of lipoxin A4 on chemotaxis and degranulation of human eosinophils stimulated by platelet-activating factor and N-formyl-L-methionyl-L-leucyl-L-phenylalanine.

Lipoxins are trihydroxytetraene metabolites derived through a double lipoxygenation of arachidonic acid. Lipoxin A4 (LXA4) was prepared by total chemical synthesis, and its capacity to modulate eosinophil migration has been evaluated. LXA4 is a weak and partial chemotactic agent; at 10(-6) M, it achieved about 20% of the response of 10(-6) M platelet-activating factor (PAF).

Structure/activity relationship of leukotriene B4 and its structural analogues in chemotactic, lysosomal-enzyme release and receptor-binding assays.

The biological activities of chemically synthesized leukotriene B4 and eight structural analogues have been studied using chemotaxis, lysosomal-enzyme release and receptor-binding assays on human neutrophils. The results show that increasing the number of double bonds between C14 and C20, having triple bonds at C6 or C14, substitution of the primary carboxyl group at C1, changing the geometry of the double bond at C6 from the cis to trans configuration and changing the chirality of the hydroxyl group at C12 from the R to the S configuration result in substantial loss of both biological activity and the capacity to bind to the LTB4 recognition site in parallel. We suggest that the functional epitopes of 5S,12R-dihydroxy-6,14-cis-8,10-trans-icosatetraenoic acid (LTB4) are either the same, or reside in the same domain as the binding site for the LTB4 receptor.