TLR2 Signaling Is Critical for <i>Mycoplasma pneumoniae</i>-Induced Airway Mucin Expression

Chu, Hong Wei; Jeyaseelan, Samithamby; Rino, John G.; Voelker, Dennis R.; Wexler, Rachel B.; Campbell, Krista; Harbeck, Ronald J.; Martin, Richard J.

doi:10.4049/jimmunol.174.9.5713

Cited by 92 publications

(97 citation statements)

References 23 publications

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“…Since all of these reagents are expected to induce NF-kB via TLR2 signaling (Chu et al, 2005), their functionality was confirmed by their ability to activate an NF-kBdependent reporter in cells expressing TLR2/TLR6 ( Figure 2c). Although all of the prepared mycoplasmal components activated NF-kB-dependent transcription, none of them, as opposed to mycoplasma infection, influenced p53 reporter activity ( Figure 2d).…”

Section: Resultsmentioning

confidence: 92%

Mycoplasma infection suppresses p53, activates NF-κB and cooperates with oncogenic Ras in rodent fibroblast transformation

et al. 2008

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Prokaryotes of the genus Mycoplasma are the smallest cellular organisms that persist as obligate extracellular parasites. Although mycoplasma infection is known to be associated with chromosomal instability and can promote malignant transformation, the mechanisms underlying these phenomena remain unknown. Since persistence of many cellular parasites requires suppression of apoptosis in host cells, we tested the effect of mycoplasma infection on the activity of the p53 and nuclear factor (NF)-jB pathways, major mechanisms controlling programmed cell death. To monitor the activity of p53 and NF-jB in mycoplasma-infected cells, we used a panel of reporter cell lines expressing the bacterial b-galactosidase gene under the control of p53-or NF-jB-responsive promoters. Cells incubated with media conditioned with different species of mycoplasma showed constitutive activation of NF-jB and reduced activation of p53, common characteristics of the majority of human tumor cells, with M. arginini having the strongest effect among the species tested. Moreover, mycoplasma infection reduced the expression level and inducibility of an endogenous p53-responsive gene, p21 waf1 , and inhibited apoptosis induced by genotoxic stress. Infection with M. arginini made rat and mouse embryo fibroblasts susceptible to transformation with oncogenic H-Ras, whereas mycoplasma-free cells underwent irreversible p53-dependent growth arrest. Mycoplasma infection was as effective as shRNA-mediated knockdown of p53 expression in making rodent fibroblasts permissive to Rasinduced transformation. These observations indicate that mycoplasma infection plays the role of a p53-suppressing oncogene that cooperates with Ras in cell transformation and suggest that the carcinogenic and mutagenic effects of mycoplasma might be due to inhibition of p53 tumor suppressor function by this common human parasite.

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Section: Resultsmentioning

confidence: 92%

Mycoplasma infection suppresses p53, activates NF-κB and cooperates with oncogenic Ras in rodent fibroblast transformation

et al. 2008

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“…Translocation of the p65 subunit of NF-B into the nucleus of lung cells was detected using an ELISA-based assay using oligonucleotides to specifically recognize the 5Ј-GGGACTTTCC-3Ј nucleotide sequence of Rel/ NF-B family (Active Motif), as described in our previous publications (22,29). A total of 20 g of nuclear extract obtained from each lung sample after 2 h post-E. coli or post-LPS challenge was added to the NF-B-specific oligonucleotide-coated 96-well plate and incubated for 1 h at room temperature.…”

Section: Nf-b Activationmentioning

confidence: 99%

Toll/IL-1 Receptor Domain-Containing Adaptor Inducing IFN-β (TRIF)-Mediated Signaling Contributes to Innate Immune Responses in the Lung during Escherichia coli Pneumonia

Jeyaseelan

Young

Fessler

et al. 2007

The Journal of Immunology

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Bacterial pneumonia remains a serious disease and is associated with neutrophil recruitment. Innate immunity is pivotal for the elimination of bacteria, and TLRs are essential in this process. Toll/IL-1R domain-containing adaptor inducing IFN-β (TRIF) is an adaptor for TLR3 and TLR4, and is associated with the MyD88-independent cascade. However, the importance of TRIF in immune responses against pulmonary bacterial pathogens is not well understood. We investigated the involvement of TRIF in a murine model of Escherichia coli pneumonia. TRIF−/− mice infected with E. coli display attenuated neutrophil migration; NF-κB activation; and TNF-α, IL-6, and LPS-induced C-X-C chemokine production in the lungs. In addition, E. coli-induced phosphorylation of JNK, ERK, and p38 MAPK was detected in bone marrow-derived macrophages (BMMs) of TRIF+/+ mice, but attenuated in BMMs of TRIF−/− mice. Furthermore, E. coli-induced TNF-α and IL-6 production was attenuated in BMMs of TRIF−/− mice. E. coli LPS-induced late MAPK activation, and TNF-α and IL-6 production were abolished in BMMs of TRIF−/− mice. Moreover, TRIF is not required for LPS-induced neutrophil influx, and keratinocyte cell-derived chemokine, MIP-2, and LPS-induced C-X-C chemokine production in the lungs. Using TLR3−/− mice, we ruled out the role of TLR3-mediated TRIF-dependent neutrophil influx during E. coli pneumonia. A TLR4-blocking Ab inhibited E. coli-induced TNF-α and IL-6 in BMMs of both TRIF−/− and TRIF+/+ mice, suggesting that TRIF-mediated signaling involves TLR4. We also found that TRIF is critical to control E. coli burden in the lungs and E. coli dissemination. Thus, rapid activation of TRIF-dependent TLR4-mediated signaling cascade serves to augment pulmonary host defense against a Gram-negative pathogen.

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“…pneumoniae is a known cause of asthma exacerbations [7][8][9] and binds to toll-like receptor (TLR)2 on airway epithelial cells to initiate an inflammatory response [4]. The present authors hypothesised that M. pneumoniae increases airway MUC5AC expression preferentially in asthma as compared with normal controls.…”

mentioning

confidence: 94%

“…CHU et al [4] demonstrated a significant increase in MUC5AC expression after ovalbumin (OVA) sensitisation and challenge in BALB/c mice, which further increased when mice were infected with M. pneumoniae after OVA. However, this finding has not been directly demonstrated in human asthma.…”

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confidence: 99%

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Mycoplasma pneumoniae induces airway epithelial cell expression of MUC5AC in asthma

Kraft¹,

Adler²,

Ingram³

et al. 2008

European Respiratory Journal

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As excess mucin expression can contribute to the exacerbation of asthma, the present authors hypothesised that Mycoplasma pneumoniae significantly induces MUC5AC (the major airway mucin) expression in airway epithelial cells isolated directly from asthmatic subjects.A total of 11 subjects with asthma and six normal controls underwent bronchoscopy with airway brushing. Epithelial cells were cultured at an air-liquid interface and incubated with and without M. pneumoniae for 48 h, and in the presence and absence of nuclear factor (NF)-kB and a toll-like receptor (TLR)2 inhibitor. Quantitative PCR was performed for MUC5AC and TLR2 mRNA. MUC5AC protein and total protein were determined by ELISA.M. pneumoniae exposure significantly increased MUC5AC mRNA and protein expression after 48 h in epithelial cells isolated from asthmatic, but not from normal control subjects, at all concentrations as compared to unexposed cells. TLR2 mRNA expression was significantly increased in asthmatic epithelial cells at 4 h compared with unexposed cells. NF-kB and TLR2 inhibition reduced MUC5AC expression to the level of the unexposed control in both groups.Mycoplasma pneumoniae exposure significantly increased MUC5AC mRNA and protein expression preferentially in airway epithelial cells isolated from asthmatic subjects. The toll-like receptor 2 pathway may be involved in this process.

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TLR2 Signaling Is Critical for Mycoplasma pneumoniae-Induced Airway Mucin Expression

Cited by 92 publications

References 23 publications

Mycoplasma infection suppresses p53, activates NF-κB and cooperates with oncogenic Ras in rodent fibroblast transformation

Mycoplasma infection suppresses p53, activates NF-κB and cooperates with oncogenic Ras in rodent fibroblast transformation

Toll/IL-1 Receptor Domain-Containing Adaptor Inducing IFN-β (TRIF)-Mediated Signaling Contributes to Innate Immune Responses in the Lung during Escherichia coli Pneumonia

Mycoplasma pneumoniae induces airway epithelial cell expression of MUC5AC in asthma

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