Differential Regulation of Neutrophil CD18 Integrin Function by Di- and Tri-Valent Cations: Manganese vs. Gadolinium

• Published in: Annals of biomedical engineering 2008-04, Vol.36 (4), p.647-660
• Main Authors: Zhang, Yi, Hayenga, Heather N., Sarantos, Melissa R., Simon, Scott I., Neelamegham, Sriram
• Format: Article
• Language: English
• Subjects: Adhesion; Biochemistry; Biological and Medical Physics; Biomechanics; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Biophysics; Cations; Cations - metabolism; Cations - pharmacology; CD18 Antigens - metabolism; Cell Adhesion - drug effects; Cell Adhesion - physiology; Cell Adhesion Molecules - metabolism; Cell Aggregation - drug effects; Cell Aggregation - physiology; Cells, Cultured; Classical Mechanics; Dose-Response Relationship, Drug; Gadolinium; Gadolinium - administration & dosage; Gadolinium - metabolism; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; Humans; Manganese; Manganese - administration & dosage; Manganese - metabolism; Neutrophil Activation - drug effects; Neutrophil Activation - physiology; Neutrophils - drug effects; Neutrophils - metabolism
• ISSN: 0090-6964; 1573-9686
• DOI: 10.1007/s10439-008-9446-7

Affinity regulation of integrin function plays an important role during both leukocyte–endothelial and leukocyte–leukocyte interactions. We compared the roles of Mn 2+ (Manganese) and Gd 3+ (Gadolinium) in regulating leukocyte CD18-integrin function. We observed that: (i) Both cations prolonged neutrophil homotypic aggregation following chemoattractant IL-8 stimulation, with Gd 3+ being effective at doses two orders of magnitude (10  μ M range) lower that Mn 2+ . (ii) While both Gd 3+ and Mn 2+ mediate homotypic cell aggregation via l -selectin and CD18 integrins, their effects on the integrin subunits, LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18), was different. Gd 3+ altered both LFA-1 and Mac-1 function, while the dominant effect of Mn 2+ was on Mac-1. This effect of Gd 3+ on LFA-1 function was confirmed in cell-free studies that measured the binding of recombinant ICAM-1 to LFA-1 immobilized on beads. (iii) Both ions augmented the binding of 327C, an antibody that recognizes active CD18 on human neutrophils, both in the presence and absence of exogenous IL-8. The effects of Mn 2+ was more pronounced since it caused 3–4-fold increase in mAb 327C binding to neutrophils compared to Gd 3+ which increased antibody binding by only ∼80%. 327C binding was partially reduced by Ca 2+ . Further, 327C binding induced by Mn 2+ did not correlate tightly with cell adhesion function. (iv) In studies that monitored intracellular Ca 2+ ([Ca 2+ ] i ), the addition of Mn 2+ but not Gd 3+ to neutrophils altered [Ca 2+ ] i levels. Overall, while both Gd 3+ and Mn 2+ stabilize high affinity CD18 mediated cell adhesion, Gd 3+ affects integrin conformation while Mn 2+ may also trigger other effects.