Legionella lipoprotein activates toll-like receptor 2 and induces cytokine production and expression of costimulatory molecules in peritoneal macrophages

Abstract

Legionella bacterium, an intracellular pathogen of mononuclear phagocytes, causes acute fatal pneumonia, especially in patients with impaired cellular immune responses. Until recently, however, the toll-like receptor (TLR) engagement of bacterial proteins derived from Legionella is uncertain. We previously showed that a 19-kDa highly conserved peptidoglycan-associated lipoprotein (PAL) of Legionella pneumophila induced the PAL-specific B cell and T cell responses in mice. In this study, we observed that the rPAL antigen of L. pneumophila, as an effector molecule, activated murine macrophages via TLR2 and produced proinflammatory cytokines such as IL-6 and TNF-α. In both BALB/c and TLR4-deficient C3H/HeJ mice, pretreatment of macrophages with anti-TLR2 mAb showed severely impaired cytokine production in response to the rPAL. In addition, in vitro the rPAL treatment increased the cell surface expression of CD40, CD80, CD86 and MHC I/II molecules. We further showed that the synthetic CpG-oligodeoxynucleotides (CpG ODN) coadministered with the rPAL enhanced IL-12 and IL-6 production and expression of CD40, CD80 and MHC II compared to the rPAL treatment alone. In conclusions, these results indicate that Legionella PAL might activate macrophages via a TLR2-dependent mechanism which thus induce cytokine production and expression of costimulatory and MHC molecules.

Peptidoglycan-associated lipoprotein ofAggregatibacter actinomycetemcomitansinduces apoptosis and production of proinflammatory cytokines via TLR2 in murine macrophages RAW 264.7in vitro

“…Our results confirmed that, similar to other bacterial lipoproteins tested in vitro [10,43,44], AaPAL-induced pro-inflammatory cytokine production by mouse macrophages is mediated by TLR2. The PAL of E. coli has also been shown to induce IL-6 and TNF-α production by mouse macrophages via TLR2 in vivo , as demonstrated by using a TLR2 knockout mouse model [22].…”

Legionella pneumophila Type II Secretion Dampens the Cytokine Response of Infected Macrophages and Epithelia

“…In the first scenario, T2S, directly or indirectly, reduces the recognition of pathogen-associated molecular patterns (PAMPs) by host surface or endosomal TLRs and/or cytosolic nucleotide binding oligomerization domain (NOD)-like receptors (NLRs) and thereby leads to a dampening of signal transduction events that result in optimal transcription of the cytokine genes. In the case of L. pneumophila, TLR2 recognizes lipopolysaccharide (LPS) and lipoprotein, TLR5 flagellin, TLR9 CpG sequences in DNA, NOD1 and NOD2 peptidoglycans, and Naip5 and Ipaf flagellin (1,3,7,9,13,23,30,45,48,53,54,60,65,75,81,92,102,103,117,120). In the second scenario, T2S compromises a step(s) in the signal transduction pathways that result after TLR/NLR ligation, including transcription itself.…”

Bordetella pertussis Proteins Dominating the Major Histocompatibility Complex Class II-Presented Epitope Repertoire in Human Monocyte-Derived Dendritic Cells

“…Also, other features driving exclusive presentation by MDDC could be involved, such as those described for the Toxoplasma gondii protein profilin, being immunodominant in the CD4 ϩ T cell response to the pathogen solely because of enhanced and selective TLR11-mediated uptake (55). TLR2 could play a role in the uptake of the lipoprotein PAL (56)(57)(58)(59)(60)(61)(62), possibly in association with the other Tol-Pal component PPP. TLR2 might also sense groES, eventually via associated compounds (63)(64)(65).…”