Journal
INFECTION AND IMMUNITY
Volume 86, Issue 4, Pages -Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/IAI.00575-17
Keywords
Candida albicans; HO-1; oral keratinocytes
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Funding
- Japan Society for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan [26463007]
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Oral keratinocytes provide the first line of host defense against oral candidiasis. We speculated that interactions of fungal cell wall components with oral keratinocytes regulate the stress response against Candida infection and examined the expression of genes induced by heat-killed Candida albicans in oral immortalized keratinocytes using a cDNA microarray technique. Of 24,000 genes revealed by that analysis, we focused on HO-1, a stress-inducible gene, as its expression was increased by both heat-killed and live C. albicans. In histological findings, HO-1 expression in the superficial layers of the oral epithelium following Candida infection was elevated compared to that in healthy epithelium. We then investigated fungal cell wall components involved in induction of HO-1 expression and found that beta-glucan-containing particles (beta-GPs) increased its expression. Furthermore, beta-glucan was observed on the surface of both heat-killed C. albicans and Candida cells that had invaded the oral epithelium. Fungal beta-GPs also promoted induction of intracellular reactive oxygen species (ROS), NADPH oxidase activation, and p38 mitogen-activated protein kinase (MAPK) phosphorylation, while those specific inhibitors inhibited the HO-1 expression induced by fungal beta-GPs. Moreover, fungal beta-GPs induced Nrf2 translocation into nuclei via p38 MAPK signaling, while the HO-1 expression induced by fungal beta-GPs was inhibited by Nrf2-specific small interfering RNA (siRNA). Finally, knockdown of cells by HO-1- and Nrf2-specific siRNAs resulted in increased beta-GP-mediated ROS production compared to that in the control cells. Our results show that the HO-1 induced by fungal beta-GPs via ROS/p38 MAPK/Nrf2 from oral keratinocytes may have important roles in host defense against the stress caused by Candida infection in the oral epithelium.
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