Altered Dendritic Cell Phenotype in Response to Leishmania amazonensis Amastigote Infection Is Mediated by MAP Kinase, ERK

Authors

Paola Mercedes Boggiatto, Iowa State UniversityFollow
Fei Jie, Iowa State University
Mousumi Ghosh, University of Miami
Katherine N. Gibson-Corley, Iowa State University
Amanda E. Ramer-Tait, University of IowaFollow
Douglas E. Jones, Iowa State UniversityFollow
Christine A. Petersen, Iowa State UniversityFollow

Document Type

Article

Date of this Version

5-2009

Citation

American Journal of Pathology, (May 2009) 174(5)

doi: 10.2353/ajpath.2009.080905

Comments

Copyright 2009, American Society for Investigative Pathology. Used by permission

Abstract

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[1] 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.