Blockade of avidity and focal clustering of β2-integrin by cysteinyl leukotriene antagonism attenuates eosinophil adhesion Angelo Y. Meliton, MD, Nilda.

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Blockade of avidity and focal clustering of β2-integrin by cysteinyl leukotriene antagonism attenuates eosinophil adhesion Angelo Y. Meliton, MD, Nilda M. Munoz, MS, Alan R. Leff, MD Journal of Allergy and Clinical Immunology Volume 120, Issue 6, Pages 1316-1323 (December 2007) DOI: 10.1016/j.jaci.2007.07.038 Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Effect of montelukast or AA861 on surface CD11b expression (A-C) or avidity of CD11b (D-F) caused by 10−7 mol/L LTB4, 10 ng/mL IL-5, or 100 ng/mL eotaxin-1 (n = 4 donors). ∗P < .05 versus baseline CD11b or LTB4-activated cells (Fig 1, D); ∗∗P < .02 versus baseline CD11b or LTB4-activated cells (Fig 1, D); †P < .01 versus baseline CD11b. Journal of Allergy and Clinical Immunology 2007 120, 1316-1323DOI: (10.1016/j.jaci.2007.07.038) Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Effect of montelukast or AA861 on β2-integrin–mediated adhesion. Eosinophils (n = 6 donors) were pretreated with montelukast, AA861, TFMK, or LTB4-DMA before LTB4(A-C), IL-5 (D-F), or eotaxin-1 (D-F) activation. †P < .01 versus unstimulated cells (us) versus TFMK versus LTB4-DMA; ∗P < .05 versus LTB4-activated cells; ∗∗P < .02 vs LTB4-activated cells and †P < . 01 versus unstimulated cells versus TFMK. Journal of Allergy and Clinical Immunology 2007 120, 1316-1323DOI: (10.1016/j.jaci.2007.07.038) Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Effect of montelukast or AA861 on stimulated focal clustering of CD11b. Eosinophils (n = 3 donors) were preincubated with montelukast (D-F) or AA861 (G-I) for 30 minutes before activation with LTB4(A), IL-5 (B), or eotaxin-1 (C). J, Naive eosinophils were stained with IgG1 antibody. K, baseline CD11b was stained with anti-CD11b mAb, as described in the Methods section. Journal of Allergy and Clinical Immunology 2007 120, 1316-1323DOI: (10.1016/j.jaci.2007.07.038) Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 A, Effect of montelukast, AA861, or LTB4-DMA on β2-integrin adhesion caused by exogenous LTD4. Data represent means ± SEMs (n = 3 donors). †P < .01 versus unstimulated cells (us); ∗P < .05 versus LTD4. B, Effect of LTB4, IL-5, or eotaxin-1 on LTC4 synthesis (n = 6 donors). ∗∗P < .02 versus unstimulated cells (us) versus IL-5 versus eotaxin-1. Journal of Allergy and Clinical Immunology 2007 120, 1316-1323DOI: (10.1016/j.jaci.2007.07.038) Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Effect of montelukast or AA861 on ERK-1/2 phosphorylation. Eosinophils were pretreated with increasing concentrations of montelukast or AA861 before LTB4(A), IL-5 (B), or eotaxin-1 (C) activation and determination of ERK-1/2 phosphorylation. Immunoblotting was performed with a specific mAb for phosphorylated ERK-1/2, as described in the Methods section. Journal of Allergy and Clinical Immunology 2007 120, 1316-1323DOI: (10.1016/j.jaci.2007.07.038) Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Postulated schema of cysLT synthetic and signaling pathways regulating integrin adhesion. 1, Activation of inflammatory cells causes LTB4 synthesis, binds to the LTB4 receptor, and causes subsequent activation of gIVaPLA2. 2, GIVaPLA2 hydrolyzes membrane phospholipids to produce lysophospholipids and free fatty acids, including arachidonic acid. 3, Conversion of LTA4 to LTB4 and cysLTC4 occurs. LTC4 is actively transported into the blood, where it is converted to LTD4(4) and binds to cysLT1R (5) on eosinophils. 6, Montelukast, a cysLT1R antagonist, blocks conformational change of CD11b (Fig 1, right), eosinophil adhesion to ICAM-1 (Fig 2), and focal clustering of CD11b (Fig 3). Eosinophils independently produce cysLTs for autocrine or paracrine cell activation, resulting in an amplification of inflammation. EOS, Eosinophils. Journal of Allergy and Clinical Immunology 2007 120, 1316-1323DOI: (10.1016/j.jaci.2007.07.038) Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions