title: Differential regulation of proinflammatory cytokine expression by mitogen-activated protein kinases in macrophages in response to intestinal parasite infection.
abstract: 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 1β (IL-1β), IL-6, and tumor necrosis factor alpha (TNF-α), 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-α and mRNA expression of IL-1β. 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-1β and TNF-α. 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.
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore.
authors.forename: Mei Xing
authors.initials: MX
authors.lastname: Lim
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore.
authors.forename: Chin Wen
authors.initials: CW
authors.lastname: Png
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore.
authors.forename: Crispina Yan Bing
authors.initials: CY
authors.lastname: Tay
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Joshua Ding Wei
authors.initials: JD
authors.lastname: Teo
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore.
authors.forename: Huipeng
authors.initials: H
authors.lastname: Jiao
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Norbert
authors.initials: N
authors.lastname: Lehming
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore mictank@nus.edu.sg miczy@nus.edu.sg.
authors.forename: Kevin Shyong Wei
authors.initials: KS
authors.lastname: Tan
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore mictank@nus.edu.sg miczy@nus.edu.sg.
authors.forename: Yongliang
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D016844:Blastocystis / Q000276:immunology*; D016776:Blastocystis Infections / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000276:immunology*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D046509:Tissue Culture Techniques
chemical_list: D016207:Cytokines; D020929:Mitogen-Activated Protein Kinase Kinases