Altered dendritic cell phenotype in response to Leishmania amazonensis amastigote infection is mediated by MAP kinase, ERK.
Initiation of productive immune responses against Leishmania depends on the successful transition of dendritic cells (DC) from an immature to a mature phenotype. This process is characterized by high CD40 surface expression as well as interleukin-12 production, which are frequently seen in response to L. major infection. In vivo footpad infection of C3HeB/FeJ mice for 7 days with L. amazonensis promoted an immature CD11c(+) DC phenotype characterized by both significantly low CD40 surface expression and significantly decreased interleukin-12p40 production compared with L. major infection of these same mice. In vitro infection of bone marrow-derived dendritic cells with L. amazonensis amastigotes resulted in rapid and significant phosphorylation of the mitogen activated protein kinase, extracellular signal-regulated kinase 1/2, observed within minutes of exposure to the parasite. Infection with L. amazonensis promastigotes led to increased 1/2 phosphorylation after 4 hours of infection compared with L. major infection, which correlated with promastigote transformation into amastigotes. Treatment of bone marrow-derived dendritic cells with a mitogen activated protein kinase kinase-specific inhibitor, PD98059, led to regained surface CD40 expression and interleukin-12p40 production following L. amazonensis amastigote infection compared with non-treated, infected DC. Treatment of L. amazonensis-infected mice with the highly-specific mitogen activated protein kinase kinase inhibitor, CI-1040, enhanced surface CD40 expression on CD11c(+) DC obtained from the draining lymph node. L. amazonensis amastigotes, through activation of extracellular signal-regulated kinase 1/2, inhibit the ability of DC to undergo proper maturation both in vitro and in vivo.
Department of Veterinary Pathology, Iowa State University, Ames, Iowa 50011, USA.
Paola Mercedes
PM
Boggiatto
Fei
F
Jie
Mousumi
M
Ghosh
Katherine Nicole
KN
Gibson-Corley
Amanda Ellen
AE
Ramer-Tait
Douglas Elliot
DE
Jones
Christine Anne
CA
Petersen
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D039521:CD11c Antigen / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000469:parasitology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D019084:Fluorescent Antibody Technique, Indirect; D006790:Host-Parasite Interactions; D015151:Immunoblotting; D007891:Leishmania / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H; D016513:Mice, SCID; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010641:Phenotype; D010766:Phosphorylation
D039521:CD11c Antigen; D019013:CD40 Antigens; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases