Anti‐Inflammatory Cytokines Induce Lipopolysaccharide Tolerance in Human Monocytes Without Modifying Toll‐Like Receptor 4 Membrane Expression

Abstract

Toll-like receptor 4 (TLR4) participates in innate immunity by detecting lipopolysaccharides (LPS) of Gram-negative bacterial cell walls. TLR4 macrophage expression in mice is modulated by LPS. This fact constitutes, at least partially, the molecular basis for LPS tolerance. Very recently, the effect of interferon-g (IFN-g), a pro-inflammatory cytokine, has been described on TLR4 membrane expression of human monocytes. IFN-g up-regulates TLR4 expression and antagonizes the LPS-induced TLR4 down-regulation. These data prompted us to study the expression of membrane TLR4 in human monocytes in which LPS tolerance was induced by LPS and by anti-inflammatory cytokines [interleukin-10 (IL-10) and transforming growth factor b1 (TGFb1)]. Data concerning this latter model, and more specifically, the effect of antiinflammatory cytokines over TLR4 expression, are not available at present. We show here that membrane TLR4 expression in human monocytes falls after LPS exposure. The effect was prolonged for 12 h, but then expression returned to normal levels. The incubation of human monocytes with IL-10, TGFb1 or a mixture of both induces no alterations in membrane TLR4 expression. However, these cytokines are able to substitute the tolerizing LPS exposure in order to induce LPS tolerance. Our data help to achieve a better understanding of the way cytokines control the cellular expression of TLR.

Protective effects and mechanisms of mogroside V on LPS-induced acute lung injury in mice

“…*p50.05, **p50.01 versus LPS group. such as TNF-a, IL-1b and IL-6, NO and PGE 2 (Moreno et al, 2004). In this study, we observed that mogroside V can inhibit the phosphorylation and degradation of IkBa, and further blocked NF-kB p65 activation.…”

Antiinflammation Effect of Human Placental Multipotent Mesenchymal Stromal Cells Is Mediated by Prostaglandin E2 via a Myeloid Differentiation Primary Response Gene 88-dependent Pathway

“…30 Our data revealed that the 15-min MFI of the LPSϩR group was significantly higher than those of the PBSϩR group (P Ͻ 0.001, fig. 6A).…”

Corticotropin-Releasing Factor and the Urocortins Induce the Expression of TLR4 in Macrophages via Activation of the Transcription Factors PU.1 and AP-1

“…In addition, we have also found that CRF peptides reversed the well-known suppressive effect of LPS on Tlr4 gene expression, indicating that the CRF peptides may affect a negative regulatory mechanism that involves down-regulation of TLR4 expression. Indeed, treatment of macrophages with LPS results in suppression of TLR4 expression first observed 2 h following stimulation (36,37). Several studies have implicated the effect of LPS on TLR4 expression as a possible mechanism leading to the development of macrophage tolerance toward further LPS stimulation and to the containment of the inflammatory response (36,37), although macrophage tolerance is also regulated at the level of TLR4 signaling (38).…”

“…Indeed, treatment of macrophages with LPS results in suppression of TLR4 expression first observed 2 h following stimulation (36,37). Several studies have implicated the effect of LPS on TLR4 expression as a possible mechanism leading to the development of macrophage tolerance toward further LPS stimulation and to the containment of the inflammatory response (36,37), although macrophage tolerance is also regulated at the level of TLR4 signaling (38). However, CRF peptides do not appear to exert any effect of their own on proinflammatory cytokine production by RAW 264.7 macrophages or by primary mouse macrophages; they most probably only modify macrophage response augmenting an already established inflammation by increasing the sensitivity of macrophages to inflammatory insults (11).…”