CD11/CD18 Leukocyte Integrins: New Signaling Receptors for Bacterial Endotoxin

Abstract

Exaggerated responses by phagocytes to bacterial endotoxin [lipopolysaccharide (LPS)] may result in the sepsis syndrome. While a number of LPS-binding proteins have been identified on immune cells, only CD14 has been definitively shown to be involved in signal transduction in response to LPS. The β2 leukocyte integrins are a family of transmembrane receptors whose expression is restricted to leukocytes. Among their many functions, the β2 integrins are phagocytic receptors that bind a variety of bacterial products, including LPS. We hypothesize that this binding results in signal transduction. Chinese hamster ovary (CHO) fibroblast cell lines expressing the CD11a/CD18 or CD11b/CD18 antigen were engineered by gene transfection. The cell lines were stimulated with LPS. LPS-induced nuclear translocation of nuclear factor kappa B (NF-κB) was analyzed by electrophoretic mobility shift assay. Heterologous expression of CD11a/CD18 and CD11b/CD18 in otherwise LPS-nonresponsive fibroblasts imparted the ability to respond to LPS. Responses to LPS were observed at levels of LPS of 100 ng/ml, as were responses to whole Gram-negative bacteria. The CD11/CD18 leukocyte integrins mediate cellular responses to the LPS component of Gram-negative bacteria. CD11/CD18-mediated responses of cells to LPS are likely to affect the phagocytosis, intracellular trafficking, and killing of invading bacteria as well as to help mediate cytokine responses during endotoxemia. The development of novel therapies to prevent the end-organ damage frequently observed during sepsis will require an understanding of these complex cellular events.