Role of extracellular signal-regulated kinases 1 and 2 and p38 mitogen-activated protein kinase pathways in regulating replication of Penicillium marneffei in human macrophages |
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| Institution: | 1. Department of Dermatology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 West Yanjiang Road, Guangzhou 510120, China;2. Infectious Disease Division, Alpert Medical School and Brown University, Rhode Island Hospital, RI, USA;1. Unité de Génétique Moléculaire des Bunyavirus, Institut Pasteur, 25 rue du Dr Roux, Paris, France;2. Unité Interactions Moléculaires Flavivirus-Hôtes, Institut Pasteur, 25 rue du Dr Roux, Paris, France;1. Department of Medical Environmental Biology and Tropical Medicine, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do 200-701, Republic of Korea;2. Department of Parasitology and Tropical Medicine, Seoul National University College of Medicine, and Institute of Endemic Disease, Seoul National University Medical Research Center, Seoul 110-799, Republic of Korea;3. Seoul National University Bundang Hospital, Seongnam 463-707, Republic of Korea;4. Department of Microbiology and Immunology, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do 200-701, Republic of Korea;5. Division of Malaria Research, Proteo-Science Center, Ehime University, Matsuyama, Ehime 790-8577, Japan;1. Department of Immunology, Basic Medical College, Hebei Medical University, Shijiazhuang 050017, China;2. Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Institute of Medical Microbiology, Fudan University, Shanghai 200032, China;3. Third Hospital of Hebei Medical University, Shijiazhuang 050000, China;1. Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan;2. AIDS Clinical Center, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan |
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| Abstract: | Penicillium marneffei (P. marneffei) is a human pathogen which persists in macrophages and threatens the immunocompromised patients. To elucidate the mechanisms involved, we investigated the role of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and p38 mitogen-activated protein kinase (p38) pathways in cytokine expression, phagosome–lysosome fusion and replication of P. marneffei in P. marneffei-infected human macrophages. Analysis of both ERK1/2 and p38 showed rapid phosphorylation in response to P. marneffei. Using specific inhibitors of p38 (SB203580) and MAP kinase kinase-1 (PD98059), we found that ERK1/2 and p38 were essential for P. marneffei-induced tumor necrosis factor-α production, whereas p38, but not that of ERK, was essential for IL-10 production. Furthermore, the presence of PD98059 always decreased phagosomal acidification and maturation and increased intracellular multiplication of P. marneffei, whereas the use of SB203580 always increased phagosomal acidification and maturation and decreased intracellular replication. These data suggest that a proper balance of between ERK1/2 and p38 may play an important role in controlling the replication of P. marneffei. Our findings further indicate a novel therapeutic avenue for treating P. marneffei by stimulating ERK1/2 or activating ERK1/2-dependent mechanisms. |
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| Keywords: | Macrophages Tumor necrosis factor-α ERK 1/2 p38 |
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