<i>Candida albicans</i> Induces Selectively Transcriptional Activation of Cyclooxygenase-2 in HeLa Cells: Pivotal Roles of Toll-Like Receptors, p38 Mitogen-Activated Protein Kinase, and NF-κB

Deva, Rupal; Shankaranarayanan, Pattabhiraman; Ciccoli, Roberto; Nigam, Santosh

doi:10.4049/jimmunol.171.6.3047

Cited by 71 publications

(60 citation statements)

References 54 publications

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“…Our data demonstrate that p38, like NF-B, is activated in a delayed kinetic upon exposure to C. albicans. This finding is in agreement with a recent report studying HeLa cells (43). The kinetics also matches findings from previous studies using LPS (39) and nickel compounds (21) as endothelial activators.…”

Section: Discussionsupporting

confidence: 93%

Candida albicans Triggers Activation of Distinct Signaling Pathways to Establish a Proinflammatory Gene Expression Program in Primary Human Endothelial Cells

Müller

Viemann²,

Schmidt

et al. 2007

The Journal of Immunology

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Endothelial cells (EC) actively participate in the innate defense against microbial pathogens. Under unfavorable conditions, defense reactions can turn life threatening resulting in sepsis. We therefore studied the so far largely unknown EC reaction patterns to the fungal pathogen Candida albicans, which is a major cause of lethality in septic patients. Using oligonucleotide microarray analysis, we identified 56 genes that were transcriptionally up-regulated and 69 genes that were suppressed upon exposure of ECs to C. albicans. The most significantly up-regulated transcripts were found in gene ontology groups comprising the following categories: chemotaxis/migration; cell death and proliferation; signaling; transcriptional regulation; and cell-cell contacts/intercellular signaling. Further examination of candidate signaling cascades established a central role of the proinflammatory NF-κB pathway in the regulation of the Candida-modulated transcriptome of ECs. As a second major regulatory pathway we identified the stress-activated p38 MAPK pathway, which critically contributes to the regulation of selected Candida target genes such as CXCL8/IL-8. Depletion of MyD88 and IL-1R-associated kinase-1 by RNA interference demonstrates that Candida-induced NF-κB activation is mediated by pattern recognition receptor signaling. Additional experiments suggest that C. albicans-induced CXCL8/IL-8 expression is mediated by TLR3 rather than TLR2 and TLR4, which previously have been implicated with MyD88/IκB kinase-2/NF-κB activation by this fungus in other systems. Our study provides the first comprehensive analysis of endothelial gene responses to C. albicans and presents novel insights into the complex signaling patterns triggered by this important pathogen.

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Section: Discussionsupporting

confidence: 93%

Candida albicans Triggers Activation of Distinct Signaling Pathways to Establish a Proinflammatory Gene Expression Program in Primary Human Endothelial Cells

Müller

Viemann²,

Schmidt

et al. 2007

The Journal of Immunology

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“…COX-2 has been shown to be induced by viral, bacterial, fungal and parasitic infections [17][18][19][20][21][22]. Studies in viral infections have shown that inhibition of COX-2 is beneficial to the host [17].…”

Section: Discussionmentioning

confidence: 99%

Bacterial clearance of Pseudomonas aeruginosa is enhanced by the inhibition of COX‐2

et al. 2007

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Prostanoids generated by COX‐2 are involved in the regulation of inflammation but their exact role in the innate immune response has not been defined. We investigated whether COX‐2 is involved in host defense against Pseudomonas aeruginosa pneumonia. In vitro studies, in a macrophage cell line, showed that cytotoxic strain of P aeruginosa (PA103) induced significant COX‐2 protein expression and enzymatic function. In vivo data showed that infection with PA103 increased COX‐2 protein production in whole lung tissue compared to mice that were infected with mutant bacteria that lack ExoU (ΔU) or ExoU and ExoT (ΔUT). COX‐2–/– mice had accentuated clearance of cytotoxic P. aeruginosa from the lungs. We further tested the effects of COX‐2 products such as prostaglandin E2 on the function of phagocytic cells. Our studies indicate that prostaglandin E2 may be involved through interacting with the EP2 receptors in modulating the host response because treatment of macrophages with prostaglandin E2 suppressed production of reactive oxygen species. Furthermore there was enhanced bacterial clearance in EP2 receptor–/– mice compared to the wild‐type controls. Thus it is possible that inhibition of COX‐2 or EP2 receptors could be an effective adjunctive treatment for severe or resistant P. aeruginosa pneumonia.

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“…This is of importance as (1) real life exposures are more like to involve mixtures of chemical and microbial agents, and (2) induction of COX-2 plays an important role in the production of immune-modulators and is widely recognized as having an important role in the onset of inflammation in the lung (39,(48)(49)(50). The findings that COX-2 contributes to the synergistic production of CXCL8 and inhibition of CXCL10 in HLF present a potential mechanism whereby exposure to PM-derived metals can exacerbate cellular responses to microbial stimuli and modulate pulmonary inflammation and its consequences such as fibrosis and angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Nickel Alterations of TLR2-Dependent Chemokine Profiles in Lung Fibroblasts Are Mediated by COX-2

Brant¹,

Fabisiak²

2008

Am J Respir Cell Mol Biol

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Particulate matter air pollution (PM) has been linked with chronic respiratory diseases. Real-life exposures are likely to involve a mixture of chemical and microbial stimuli, yet little attention has been paid to the potential interactions between PM components (e.g., Ni) and microbial agents on the development of inflammatory-like conditions in the lung. Using the Toll-like receptor (TLR)-2 agonist MALP-2 as a lipopeptide relevant to microbial colonization, we hypothesized that nickel sensitizes human lung fibroblasts (HLF) for microbial-driven chemokine release through modulation of TLR signaling pathways. NiSO 4 (200 mM) synergistically enhanced CXCL8, yet antagonized CXCL10 mRNA expression and protein release from HLF in response to MALP-2. RT 2 -PCR pathway-focused array results indicated that NiSO 4 exposure did not alter the expression of TLRs or their downstream signaling mediators, yet significantly increased the expression of cyclooxygenase 2 (COX-2). Moreover, when NiSO 4 was given in combination with MALP-2, there was an amplified induction of COX-2 mRNA and protein along with its metabolic product, PGE2, in HLF. The COX-2 inhibitor, NS-398, attenuated NiSO 4 and MALP-2-induced PGE2 and CXCL8 release and partially reversed the NiSO 4 -dependent inhibition of MALP-2-induced CXCL10 release from HLF. These data indicate that NiSO 4 alters the pattern of TLR-2-dependent chemokine release from HLF via a COX-2-mediated pathway. The quantitative and qualitative effects of NiSO 4 on microbial-driven chemokine release from HLF shed new light on how PM-derived metals can exacerbate respiratory diseases.Keywords: COX-2; nickel; inflammation; chemokines; fibroblasts Particulate matter air pollution (PM) is a contributing risk factor for many adverse health effects, including respiratory diseases (1). Real-life scenarios are likely to involve exposures not only to chemical stresses such as PM, but microbial stimuli as well. While much attention has been paid to microbial-driven inflammation in the lung, limited information is available regarding the potential interactions between PM exposures and microbial stress on respiratory function. There are reports, however, of increased numbers of hospitalizations for respiratory disorders including infections on days of increased levels of PM (2). In support of these epidemiologic findings, several rodent models have shown PM exposure can increase susceptibility to infectious bacteria such as Listeria monocytogenes and Streptococcus pneumoniae (3, 4).Recent evidence suggests that colonization with species originally considered commensal and not causing overt disease (e.g., Mycoplasma fermentans) also has the potential to interact with other stimuli and/or alter biological responses in infected host cells (5, 6). For example, we have previously shown that exposure of human lung fibroblast cells (HLF) to M. fermentans synergistically enhances the release of IL-6 by PM in the form of residual oil fly ash (ROFA) compared to either stimulus alone (7). It is well recognized t...

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Candida albicans Induces Selectively Transcriptional Activation of Cyclooxygenase-2 in HeLa Cells: Pivotal Roles of Toll-Like Receptors, p38 Mitogen-Activated Protein Kinase, and NF-κB

Cited by 71 publications

References 54 publications

Candida albicans Triggers Activation of Distinct Signaling Pathways to Establish a Proinflammatory Gene Expression Program in Primary Human Endothelial Cells

Candida albicans Triggers Activation of Distinct Signaling Pathways to Establish a Proinflammatory Gene Expression Program in Primary Human Endothelial Cells

Bacterial clearance of Pseudomonas aeruginosa is enhanced by the inhibition of COX‐2

Nickel Alterations of TLR2-Dependent Chemokine Profiles in Lung Fibroblasts Are Mediated by COX-2

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