The Cholesterol Content of the Plasma Membrane as a Regulator of CD14 Dependent Signal Transduction

Abstract

Lipopolysaccharide (LPS) is known to bind to several surface molecules on various cells. The best characterized LPS-binding protein is CD14, strongly expressed in the majority of monocytes. Since CD14 is a glycosylphosphatidyl-inositol (GPI)-anchor protein without a cytoplasmic tail, it has been suggested that additional signalling receptors co-associate with CD14 in order to initiate signal transduction cascades.Here we show that after ligand binding in human blood monocytes, the b2-integrin CD11b/CD18 forms clusters with CD14, after ligand binding, Thus, in response to LPS stimulation a receptor complex is formed in the plane of the plasma membrane which may be of central importance for cellular responses to LPS. We also show that another physiologically relevant ligand of CD14, ceramide, which is structurally similar to LPS, induces a complex of CD14 and CD11b/CD18 after binding to CD14.

Monoclonal Antibody to CD14, TLR4, or CD11b: Impact of Epitope and Isotype Specificity on ROS Generation by Human Granulocytes and Monocytes

“…TLR4 operates with the assistance of other cell surface receptors which are assembled in the LPS-induced “receptor cluster” [ 6 ]. Besides CD14 and TLR4, other receptors including the β 2 integrin CD11b/CD18 and Fc γ Rs (CD16A, CD32, and CD64) have been also detected as constituents of monocyte LPS-induced “receptor cluster” [ 41 , 42 , 44 ].…”

“…Thus, blockage of Vav-1 in human PMNs can abrogate association of p67 phox with NADPH oxidase thereby suppressing O 2 ·− /ROS production [ 134 ]. This suppressive effect of CD32A and mIgG1 might be reversed by LPS-induced assembly and stabilization of TLR4, CD11b/CD18, and Fc γ Rs in lipid rafts followed by the activation of classical ITAM signaling [ 11 , 41 , 44 , 79 , 139 ]. Since PMNs express very low levels of CD32B, an impact of its involvement in the inhibitory effectiveness of mIgG1 antibodies should be negligible [ 140 ].…”

“…Thus, only “inside-out” primed integrins exhibit increased ligand-binding avidity and initiate “outside-in” signaling by themselves. CD11b/CD18 has been detected in the LPS-induced “receptor cluster” on monocytes and can act as a signaling partner for such receptors as FPR1 and CD14 [ 44 , 106 , 150 , 152 , 153 ]. CD11b/CD18 can be found also in association with Fc γ Rs, but the consequences of these functional interactions are not fully understood.…”