Tolerance to Pyrogens

Abstract

In humans or experimental animals, the repeated confrontation with lipopolysaccharides (LPS) from gram-negative bacteria, but not with muramyl dipeptide (MDP) from gram-positive bacteria, leads to attenuation of almost all pathophysiologic effects mediated by proinflammatory cytokines. Our experiments in guinea pigs and rats demonstrate that attenuation of the febrile response during the development of LPS tolerance is associated with a reduced production of cytokines rather than a decrease in responsiveness to cytokines. Cross-tolerance experiments demonstrate that different stimuli influencing LPS-induced tumor necrosis factor (TNF) release and nitric oxide (NO) synthesis can modify the development of tolerance. On the other hand, the lack of cross-tolerance between LPS and MDP indicates that MDP can activate the cytokine cascade and induce the febrile response in animals tolerant to LPS. This may indicate distinct receptors and signal pathways for LPS and MDP, leading to activation of the cytokine cascade. LPS tolerance has also been demonstrated in ex vivo and in vitro studies. In cultures of monocytes, diminished synthesis of TNF and NO reported after LPS restimulation could be prevented and reversed by interferon and granulocyte-macrophage colony-stimulating factor. These findings add an additional hypothesis in tolerance development.

Synergy and Cross-Tolerance Between Toll-Like Receptor (TLR) 2- and TLR4-Mediated Signaling Pathways

“…Pretreatment with bacterial DNA induced LPS tolerance; however, LPS pretreatment was less effective in induction of tolerance to bacterial DNA (34,38). Likewise, although muramyl dipeptide pretreatment significantly reduced the serum level of inflammatory cytokines after administration of LPS, LPS treatment did not reduce inflammatory cytokine production after muramyl dipeptide administration in guinea pig (2). Thus, LPS treatment has been shown to be less effective in induction of tolerance to other bacterial components.…”

“…These include bacterial lipopeptides, peptidoglycan, muramyl dipeptide from Gram-positive bacteria, and bacterial DNA containing unmethylated CpG motif. These bacterial components have also been shown to induce tolerance to the subsequent stimulation (2)(3)(4).…”

The immunomodulator ginsan induces resistance to experimental sepsis by inhibiting Toll‐like receptor‐mediated inflammatory signals

“…Interestingly, the fact that ginsan alone stimulates TLR in normal macrophages (unpublished data), but down-regulates them in septic macrophages, leads us to speculate that ginsan can induce tolerance against a variety of septic challenges. In support of this hypothesis, endotoxin or LPS tolerance is a well-established phenomenon in which pre-exposure to a sublethal dose of LPS blunts subsequent lethal LPS-induced mortality, and this effect was closely associated with diminished production of proinflammatory cytokines [34,35]. In addition to LPS tolerance, several non-LPS bacterial cell wall components, including bacterial lipoprotein (BLP), also induce tolerance [36,37].…”

Involvement of IRAK-M in Peptidoglycan-induced Tolerance in Macrophages

“…It is an adaptive host response that may represent an essential regulatory mechanism during Gram-negative bacterial infection, but it may also promote subsequent infection in survivors of septic shock (5)(6)(7)(8)(9)(10)(11). Monocytes from septic patients have a reduced capacity to release TNF-␣, IL-1␤, IL-6, IL-10, and IL-12 (12)(13)(14).…”