Associate editor: M. KimuraMolecular mechanisms of macrophage activation and deactivation by lipopolysaccharide: roles of the receptor complex
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.
Section snippets
Role of CD14 in the lipopolysaccharide receptor complex
CD14, a 55-kDa glycoprotein, is an essential component of the LPS receptor complex (Wright et al., 1990b). CD14 is present in soluble form in blood or a glycosylphosphatidylinositol-linked form on myeloid lineage cells. Enterobacterial LPS first binds to a serum LPS binding protein (LBP), which in turn transfers a LPS monomer from the bacterial cell wall to membrane-bound CD14 on monocytes and myeloid cells, subsequently causing LPS responses (Schumann et al., 1990). CD14-negative cells such as
Modulation of the lipopolysaccharide receptor complex
Macrophages produce classical inflammatory cytokines immediately after treatment with LPS and then produce other cytokines such as IL-18 and macrophage migration inhibitory factor (MIF) much later after the stimulation. These proinflammatory cytokines amplify the initial signal and are responsible for orchestrating a complex network of secondary responses.
MIF-deficient mice are hyporesponsive to LPS and Gram-negative bacteria (Bozza et al., 1999), and antibody against MIF is fully protective
Role of integrin CD11/CD18
The CD11/CD18 β2 integrins are a family of heterodimeric glycoproteins expressed on leukocytes. The CD18 β-subunit noncovalently associates with 1 of 3 subunits (e.g., CD11a [LFA-1], CD11b [Mac-1, CR3], or CD11c [CR4]). Macrophages predominantly express CD11b/CD18 heterodimers. Although CD11b/CD18 was originally identified as a LPS receptor, monocytes and macrophages from CD18-deficient patients produce normal levels of TNF-α and IL-1β, suggesting that CD18 is not essential for cellular
Endotoxin shock and endotoxin tolerance
The inflammatory response is critical to control the growth of pathogenic microorganisms. However, excessive cytokine production is harmful to the host and can even be fatal (Beutler et al., 1985). Gram-negative sepsis is a major cause of death throughout the world. It is well known that experimental animals and humans become refractory to a subset of endotoxin-driven responses after an initial sublethal exposure to endotoxin. This phenomenon, termed endotoxin tolerance (also called LPS
Lipid A antagonist as a potential therapeutic agent for septic shock
Although numerous therapeutic interventions for septic shock have been carried out, this review will focus on the lipid A antagonists that compete with the pharmacological actions of pathological LPS by blocking the LPS receptor complex.
Tanamoto et al. (1984) reported LPS antagonists for the first time. They found that some chemically synthesized lipid A analogues, which are structurally distinct from native lipid A regarding the position of the fatty acid and hence endotoxically inactive in
Conclusions and perspectives
The identification and characterization of molecules in the LPS receptor complex as well as the LPS activation cluster have extended tremendously our understanding of LPS sensoring and LPS signaling. In addition, novel mechanisms for LPS tolerance have been postulated. Sepsis is the leading cause of death in critically ill patients, and several therapies have been proposed. A blockade of the LPS receptor complex using LPS antagonists is one of the most promising strategies. Several adaptor
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