Upregulation of Toll-Like Receptor 2 Gene Expression in Macrophage Response to Peptidoglycan and High Concentration of Lipopolysaccharide Is Involved in NF-κB Activation

Abstract

Several observed clinical and immunological similarities between lipopolysaccharide (LPS), an integral component of the outer cell membranes of gram-negative bacteria, and peptidoglycan (PGN), a component of the cell walls of gram-positive bacteria, suggest that the two bacterial components initiate analogous signaling pathways after being recognized by monocytes/macrophages (8,12,15,33,49). These signaling pathways are thought to be cascades for NF-B activation. Activated NF-B controls the transcription of numerous genes including those involved in cell proliferation, transformation, inflammation, and survival (2, 3, 32). Besides activating NF-B, LPS and PGN similarly activate other transcription factors, such as CREB/ATF and AP-1, in a membrane CD14 (mCD14)-dependent or -independent manner (13, 14, 18). The real dissimilarity between their signal pathways was revealed recently, and their initial discrimination by different Drosophila melanogaster Toll proteins, evolutionarily conserved from fruit flies to humans, is under way (4, 21). To date, six human Toll-like receptors (TLRs) have been cloned (40,44). Of these, TLR2 and TLR4 have been extensively investigated and are thought to be signal transducers of PGN and LPS, respectively (7,24,32,35,50).TLR2, predominantly distributed in monocytes/macrophages and polymorphonuclear cells (PMNs) (34), had been thought to be a signal transducer of LPS. Conclusive evidence mainly came from the following data. First, the overexpression of TLR2 in human embryonic 293 cells conferred LPS responsiveness on the cells, resulting in NF-B activation and interleukin-8 (IL-8) mRNA expression. Second, the cotransfection of TLR2 with mCD14 synergistically enhanced LPS signaling (24, 50). Third, the putative complex of mCD14-TLR2 after LPS exposure to the cotransfected cells was found to initiate an IL-1 receptor-like NF-B signaling cascade (51). Fourth, the LPS-elevated expression of the TLR2 gene, as measured by reverse transcription-PCR (RT-PCR), was observed in human monocytes and in mouse peritoneal macrophages (31,50). Like the transcriptional expression of TLR2, the transcriptional expression of mCD14 in human monocytes is upregulated by LPS (30). The elevated expression of the TLR2 and mCD14 genes undoubtedly contributes to the resensitization of macrophages to invasive pathogens. However, the finding that TLR4 but not TLR2 senses LPS has challenged the above conclusions.TLR4 is predominantly present in monocytes/macrophages, PMNs, dermal microvessel and umbilical vein endothelial cells, and intestinal epithelial cells (6,9,34). Several studies have shown that a TLR4 transfectant initiates a series of events for NF-B activation, as does TLR2 (7,32). Moreover, the macrophages and B cells from mice (C3H/HeJ) that have a TLR4 mutation in the intracellular domain consisting of the replacement of a conserved proline residue by histone are hyporesponsive to LPS in vitro and in vivo (22,36,38). Further evidence from TLR2 and TLR4 knockout mice has confirmed

Increased macrophage activation mediated through toll‐like receptors in rheumatoid arthritis

“…TLR-2 expression was increased on PB monocytes in response to LPS and IL-1␤ (40,41). Further, treatment of monocytes with interferon-␥ (IFN␥) resulted in increased cell surface expression of both TLR-2 and TLR-4 (18,42), and IFN␥ sensitized the monocytes to respond to LPS (43).…”

Plasmodium falciparum Infection Causes Proinflammatory Priming of Human TLR Responses

“…Ag causes an up-regulation of these receptors. Following incubation for 24 h with either LPS or Pam3Cys in vitro, TLR expression on monocytes demonstrated typical changes (24,25), with lower TLR-4 and higher TLR-2 (Table I). Following similar incubation with P.f.…”

Dendritic Cells Derived from Murine Colonic Mucosa Have Unique Functional and Phenotypic Characteristics

“…Such a phenomenon has been previously observed with human monocyte-derived DCs (49,50). In contrast, LPS stimulation has been shown to up-regulate expression of TLR2 or TLR9 by human or mouse macrophages, respectively (51,52). This discrepancy seems to be due to length of cell stimulation, where TLR expression is up-regulated initially at early time points and down-regulated at later time points.…”