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(American Journal of Pathology. 2002;160:2275-2283.)
© 2002 American Society for Investigative Pathology

Regular Articles

Lipoxins Induce Actin Reorganization in Monocytes and Macrophages But Not in Neutrophils

Differential Involvement of Rho GTPases

Paola Maderna*§, David C. Cottell{dagger}, Giovanni Berlasconi{ddagger}, Nicos A. Petasis{ddagger}, Hugh R. Brady*§ and Catherine Godson*§

From the Centre for Molecular Inflammation and Vascular Research, Mater Misericordiae Hospital, the Department of Medicine and Therapeutics,*Conway Institute of Biomolecular and Biomedical Research, and The Electron Microscopy Laboratory,{dagger}University College Dublin and Dublin Molecular Medicine Centre,§Dublin, Ireland; and the Department of Chemistry,{ddagger}University of Southern California, Los Angeles, California

Lipoxins (LXs) are endogenously produced eicosanoids that inhibit neutrophil trafficking and stimulate nonphlogistic phagocytosis of apoptotic neutrophils by monocyte-derived macrophages. In this study we assessed the effect of LXs on cell ultrastructure and actin reorganization in human leukocytes and investigated the signaling events that subserve LX bioactivity in this context. LXA4 (10-9 mol/L), the stable synthetic analogues 15-(R/S)-methyl-LXA4 and 16-phenoxy-LXA4 (10-11 mol/L), but not the LX precursor 15-(S)-HETE, induced marked changes in ultrastructure and rearrangement of actin in monocytes and macrophages. In contrast, LXA4 did not modify actin distribution in neutrophils under basal conditions and after stimulation with leukotriene B4. Blockade of Rho kinases by the inhibitor Y-27632 prevented LXA4-triggered actin reorganization in macrophages. To investigate the role of the specific small GTPases in LX-induced actin rearrangement we used THP-1 cells differentiated to a macrophage-like phenotype. THP-1 cells stimulated with LXs, but not with 15-(S)-HETE, showed an increase in membrane-associated RhoA and Rac by immunoblotting. Additionally, a twofold increase in Rho activity was seen in response to LXA4. LX-induced actin rearrangement and RhoA activation were inhibited by the cell permeable cAMP analogue 8-Br-cAMP, whereas Rp-cAMP, an inhibitor of protein kinase A, mimicked the effect of LXA4. These data demonstrate that LXs stimulate RhoA- and Rac-dependent cytoskeleton reorganization, contributing to the potential role of LXs in the resolution of inflammation.




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