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

• Published in: The American journal of pathology Vol. 174; no. 5; pp. 1818 - 1826
• Main Authors: Boggiatto, Paola Mercedes, Jie, Fei, Ghosh, Mousumi, Gibson-Corley, Katherine Nicole, Ramer-Tait, Amanda Ellen, Jones, Douglas Elliot, Petersen, Christine Anne
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.05.2009; ASIP; American Society for Investigative Pathology
• Subjects: Animals; Biological and medical sciences; Bone Marrow - metabolism; Bone Marrow - pathology; CD11c Antigen - metabolism; CD40 Antigens - metabolism; Dendritic Cells - immunology; Dendritic Cells - parasitology; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Fluorescent Antibody Technique, Indirect; Host-Parasite Interactions; Immunoblotting; Investigative techniques, diagnostic techniques (general aspects); Leishmania - immunology; Leishmania amazonensis; Medical sciences; Mice; Mice, Inbred C3H; Mice, SCID; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Mitogen-Activated Protein Kinases - metabolism; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Phenotype; Phosphorylation; Regular; Kinetoplastida; Protozoa; Dendritic cell; Immune response; Extracellular signal-regulated protein kinase; Enzyme; Transferases; Mitogen-activated protein kinase; Anatomic pathology; Phenotype; Antigen presenting cell; Amastigote; Leishmania amazonensis
• ISSN: 0002-9440; 1525-2191
• DOI: 10.2353/ajpath.2009.080905

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.