Abstract 16907: Activation of Integrin αMβ2 on Human Monocytes Regulates Alternative Activation of Macrophages: Inhibition of 15-lipoxygenase and Scavenger Receptor CD36
The alternative activation of monocytes with IL-13 and IL-4 is a host defense mechanism involved in the regulation of pro- and anti-inflammatory functions of macrophages. The purpose of this study was to analyze the role of β2 integrins (CD11/CD18), receptors responsible for monocyte migration to the site of inflammation, in regulation of IL-13-mediated monocyte activation. We focused on the analysis of expression of 15-lipoxygenase (15-LO), an important enzyme involved in the oxidation of low density lipoproteins. Previously it has been shown, that IL-13 as well as IL-4 mediate the dramatic upregulation of 15-LO on monocytes. We found that adhesion of resting monocytes through β2 integrins and inside-out activation of β2 integrins by MCP-1 did not change IL-13-stimulated 15-LO induction; however, preincubation of monocytes with the antibody MEM48, which generates full activation of β2 integrins, dramatically inhibits IL-13-induced 15-LO mRNA and protein expression. A similar effect of MEM48 antibody was also detected in IL-4 mediated 15-LO induction. In contrast, activation of β1 integrins had no effect on 15-LO level. Analysis of integrin clustering through αM, αL, αX and αD subunits demonstrated the pivotal role for integrin αMβ2 in inhibiting 15-LO expression during β2 integrin activation. IL-13 treatment also upregulates 15-LO-dependent CD36 induction on monocytes, and β2 integrin activation and αM integrin clustering dramatically inhibited CD36 mRNA and protein expression. Moreover, CD36-related foam cell formation was also inhibited after αMβ2 integrin activation. Although alternatively activated monocyte/macrophages are considered to be anti-inflammatory in nature, the 15-LO/CD36/foam cell axis suggests that this delineation is not so clear and the role of β2 integrin activation in inhibiting foam cell formation is a novel and unexpected finding, which demonstrates a potential regulatory role for the integrin αMβ2 on alternative activation of macrophages during atherogenesis.
- © 2010 by American Heart Association, Inc.