title: 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.
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.
authors.affiliation: Department of Dermatology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 West Yanjiang Road, Guangzhou 510120, China.
authors.forename: Renqiong
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Dermatology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 West Yanjiang Road, Guangzhou 510120, China.
authors.forename: Xiqing
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Dermatology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 West Yanjiang Road, Guangzhou 510120, China.
authors.forename: Sha
authors.initials: S
authors.lastname: Lu
authors.affiliation: Department of Dermatology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 West Yanjiang Road, Guangzhou 510120, China.
authors.forename: Tuan
authors.initials: T
authors.lastname: Ma
authors.affiliation: Department of Dermatology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 West Yanjiang Road, Guangzhou 510120, China.
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Huang
authors.affiliation: Infectious Disease Division, Alpert Medical School and Brown University, Rhode Island Hospital, RI, USA.
authors.forename: Eleftherios
authors.initials: E
authors.lastname: Mylonakis
authors.affiliation: Department of Dermatology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 West Yanjiang Road, Guangzhou 510120, China.
authors.forename: Yuheng
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Department of Dermatology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 West Yanjiang Road, Guangzhou 510120, China. Electronic address: xiliyan@mail.sysu.edu.cn.
authors.forename: Liyan
authors.initials: L
authors.lastname: Xi
mesh_terms: D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000378:metabolism / Q000382:microbiology; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology*; D010407:Penicillium / Q000254:growth & development* / Q000276:immunology*; D010588:Phagosomes / Q000276:immunology / Q000382:microbiology
chemical_list: D016207:Cytokines
keywords: ERK 1/2; Macrophages; Penicillium marneffei; Tumor necrosis factor-α; p38