4.4 Article

Differential Regulation of Proinflammatory Cytokine Expression by Mitogen-Activated Protein Kinases in Macrophages in Response to Intestinal Parasite Infection

期刊

INFECTION AND IMMUNITY
卷 82, 期 11, 页码 4789-4801

出版社

AMER SOC MICROBIOLOGY
DOI: 10.1128/IAI.02279-14

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  1. Office of the Deputy President, National University of Singapore
  2. Ministry of Education [MOE2010-T2-1-079]
  3. National Medical Research Council [IRG10nov091, CBRG11nov101]
  4. National Research Foundation of Singapore [NRF-CRP7-2010-03]
  5. Ministry of Education of Singapore [MOE2012 T2 101]

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Blastocystis is a common enteric protistan parasite that can cause acute, as well as chronic, infection and is associated with irritable bowel syndrome (IBS). However, the pathogenic status of Blastocystis infection remains unclear. In this study, we found that Blastocystis antigens induced abundant expression of proinflammatory cytokines, including interleukin 1 beta (IL-1 beta), IL-6, and tumor necrosis factor alpha (TNF-alpha), in mouse intestinal explants, in mouse colitis colon, and in macrophages. Further investigation utilizing RAW264.7 murine macrophages showed that Blastocystis treatment in RAW264.7 macrophages induced the activation of ERK, JNK, and p38, the three major groups of mammalian mitogen-activated protein (MAP) kinases that play essential roles in the expression of proinflammatory cytokines. ERK inhibition in macrophages significantly suppressed both mRNA and protein expression of IL-6 and TNF-alpha and mRNA expression of IL-1 beta. On the other hand, JNK inhibition resulted in reductions in both c-Jun and ERK activation and significant suppression of all three proinflammatory cytokines at both the mRNA and protein levels. Inhibition of p38 suppressed only IL-6 protein expression with no effect on the expression of IL-1 beta and TNF-alpha. Furthermore, we found that serine proteases produced by Blastocystis play an important role in the induction of ERK activation and proinflammatory cytokine expression by macrophages. Our study thus demonstrated for the first time that Blastocystis could induce the expression of various proinflammatory cytokines via the activation of MAP kinases and that infection with Blastocystis may contribute to the pathogenesis of inflammatory intestinal diseases through the activation of inflammatory pathways in host immune cells, such as macrophages.

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