Molecular mechanisms of macrophage activation and deactivation by lipopolysaccharide: roles of the receptor complex

Abstract

Bacterial lipopolysaccharide (LPS), the major structural component of the outer wall of Gram-negative bacteria, is a potent activator of macrophages. Activated macrophages produce a variety of inflammatory cytokines. Excessive production of cytokines in response to LPS is regarded as the cause of septic shock. On the other hand, macrophages exposed to suboptimal doses of LPS are rendered tolerant to subsequent exposure to LPS and manifest a profoundly altered response to LPS. Increasing evidence suggests that monocytic cells from patients with sepsis and septic shock survivors have characteristics of LPS tolerance. Thus, an understanding of the molecular mechanisms underlying activation and deactivation of macrophages in response to LPS is important for the development of therapeutics for septic shock and the treatment of septic shock survivors. Over the past several years, significant progress has been made in identifying and characterizing several key molecules and signal pathways involved in the regulation of macrophage functions by LPS. In this paper, we summarize the current findings of the functions of the LPS receptor complex, which is composed of CD14, Toll-like receptor 4 (TLR4), and myeloid differentiation protein-2 (MD-2), and the signal pathways of this LPS receptor complex with regard to both activation and deactivation of macrophages by LPS. In addition, recent therapeutic approaches for septic shock targeting the LPS receptor complex are described.

Introduction

Bacterial endotoxin (lipopolysaccharide, LPS) is a complex glycolipid composed of a hydrophilic polysaccharide moiety and a hydrophobic domain known as lipid A. LPS is a major component of the outer membrane of Gram-negative bacteria and one of the most potent microbial initiators of inflammation Raetz, 1990, Cohen, 2002. LPS activates monocytes and macrophages to produce proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1, IL-6, IL-8, and IL-12 Raetz, 1990, Cohen, 2002. Macrophages also secrete, in response to LPS, a wide variety of other biological response mediators including platelet-activating factor, prostaglandins, enzymes, and free radicals, such as nitric oxide Raetz, 1990, Cohen, 2002. Production of these inflammatory cytokines and mediators by monocytes/macrophages contributes to the efficient control of growth and dissemination of invading pathogens. However, excessive and uncontrolled production of these inflammatory cytokines and mediators may lead to serious systemic complications such as microcirculatory dysfunction, tissue damage, and septic shock with a high mortality Morrison & Ryan, 1987, Tracey et al., 1987, Ulevitch & Tobias, 1995. When monocytes/macrophages are treated with a sublethal dose of LPS, the cells become refractory to subsequent exposure to a high dose of LPS. This deactivation phenomenon is known as endotoxin tolerance or LPS desensitization.

The molecular mechanisms of LPS-induced macrophage activation and desensitization have been extensively investigated. These studies suggested the involvement of various kinases such as protein kinase A (Muroi & Suzuki, 1993), protein kinase C (Fujihara et al., 1994a), Src-related kinases (Herrera-Velit & Reiner, 1996), and the 3 classes of mitogen-activated protein kinases (MAPK): extracellular signal-regulated kinase (ERK) 1 and ERK2 (Weinstein et al., 1992), p38 MAPK (Han et al., 1994), and c-Jun N-terminal kinases (JNK) (Hambleton et al., 1996). G-proteins are also involved in LPS signal transduction (Jakway & DeFranco, 1986). Numerous inflammatory cytokines as well as mediators are expressed in LPS-stimulated macrophages through transcription factors including nuclear factor κB (NF-κB) and activator protein-1 (AP-1) Fujihara et al., 1993, Muroi et al., 1993, Guha & Mackman, 2001. Great progress has been made in the identification of molecules in the LPS receptor complex, which plays essential roles in sensoring and binding and in mediating the response to LPS. The LPS complex is composed of 3 proteins—CD14, Toll-like receptor 4 (TLR4), and myeloid differentiation protein-2 (MD-2) (Fig. 1). In this review, we will summarize the current level of understanding of the mechanisms by which LPS may dictate the activation or deactivation of macrophages by focusing on the LPS receptor complex.