Induction of inflammatory cytokines and nitric oxide in J774.2 cells and murine macrophages by lipoteichoic acid and related cell wall antigens from Staphylococcus epidermidis

Abstract

Staphylococcus epidermidis causes infections associated with medical devices including central venous catheters, orthopaedic prosthetic joints and artificial heart valves. This coagulase-negative staphylococcus produces a conventional cellular lipoteichoic acid (LTA) and also releases a shortglycerophosphate-chain-length form of LTA (previously termed lipid S) into the medium during growth. The relative pro-inflammatory activities of cellular and short-chain-length exocellular LTA were investigated in comparison with peptidoglycan and wall teichoic acid from S. epidermidis and LPS from Escherichia coli O111. The ability of these components to stimulate the production of proinflammatory cytokines [interleukin (IL)-1â, IL-6 and tumour necrosis factor (TNF)-AE] and nitric oxide was investigated in a murine macrophage-like cell line (J774.2), and in peritoneal and splenic macrophages. On a weight-for-weight basis the short-chain-length exocellular LTA was the most active of the S. epidermidis products, stimulating significant amounts of each of the inflammatory cytokines and nitric oxide, although it was approximately 100-fold less active than LPS from E. coli. By comparison the full-chain-length cellular LTA and peptidoglycan were less active and the wall teichoic acid had no activity. As an exocellular product potentially released from S. epidermidis biofilms, the short-chain-length exocellular LTA may act as the prime mediator of the host inflammatory response to device-related infection by this organism and act as the Gram-positive equivalent of LPS in Gram-negative sepsis. The understanding of the role of short-chain-length exocellular LTA in Gram-positive sepsis may lead to improved treatment strategies.

Lipoteichoic Acid Is Important in Innate Immune Responses to Gram-Positive Bacteria

“…Thus, LTA should be considered an important TLR2 ligand. LTA is readily released into culture supernatants and is abundant in them (32,57), whereas lipoproteins are primarily associated with bacteria and are not released into supernatants (45). In fact, consistent with our conclusions is the finding that the culture supernatant of the lipoprotein-deficient bacteria (⌬lgtA) is as inflammatory as wild-type bacterial culture supernatant (45).…”

“…Therefore, to evaluate the role of LTA in innate immune responses to gram-positive bacteria, we investigated the effects of inactivating LTA on the inflammatory properties of bacterial culture supernatants, which contain molecules that are shed or released from bacteria (24,26,32,46,54,57). Selective inactivation was possible since we have shown that plateletactivating factor acetylhydrolase (PAF-AH), a phospholipase A 2 , selectively inactivates staphylococcal and pneumococcal LTAs by removing their acyl-2 chain (44) but does not affect other acylated bacterial molecules, such as LPS and phosphatidylcholine (44).…”

Procalcitonin, C-Reactive Protein, Interleukin-6, and Soluble Intercellular Adhesion Molecule-1 as Markers of Postoperative Orthopaedic Joint Prosthesis Infections

“…The use of IL-6 helped to distinguish between patients with infection and those without infection; however, other studies have indicated that IL-6 is not specific for detecting bacterial infection (18,37,39). IL-6 levels remained higher than the normal range also in the patients with previous infection, although to a lesser extent compared to patients with infection.…”

“…Its soluble forms (sICAM-1), both monomeric and dimeric, are generated by proteolytic cleavage (16)(17)(18)(19). The majority of molecules that bind ICAM-l are leukocyte integrins (LFA-l and Mac-) (20)(21)(22)(23), but also other types of molecules, including fibrinogen, rhinoviruses, and erythrocytes infected by Plasmodium falciparum can bind this molecule (24)(25).…”

Virulence Factors in Methicillin-Resistant <i>Staphylococcus aureus</i> Isolated from ICU Units in Brazil

“…In animal models, lipoteichoic acid can induce features of sepsis such as delayed circulatory failure with hypotension and multiple organ failure [31]. Jones et al [32] demonstrated that the staphylococcal exocellular lipoteichoic acid is a potent activator of pro-inflammatory cytokines (TNF-a, IL-6 and IL-1) and nitric oxide in a murine macrophage cell line. The exocellular lipoteichoic acid is significantly more active than that of lipoteichoic acid, peptidoglycan or wall teichoic acid, especially for TNF-a and nitric oxide production.…”