title: Systemic IL-12 administration alters hepatic dendritic cell stimulation capabilities.
abstract: The liver is an immunologically unique organ containing tolerogenic dendritic cells (DC) that maintain an immunosuppressive microenvironment. Although systemic IL-12 administration can improve responses to tumors, the effects of IL-12-based treatments on DC, in particular hepatic DC, remain incompletely understood. In this study, we demonstrate systemic IL-12 administration induces a 2-3 fold increase in conventional, but not plasmacytoid, DC subsets in the liver. Following IL-12 administration, hepatic DC became more phenotypically and functionally mature, resembling the function of splenic DC, but differed as compared to their splenic counterparts in the production of IL-12 following co-stimulation with toll-like receptor (TLR) agonists. Hepatic DCs from IL-12 treated mice acquired enhanced T cell proliferative capabilities similar to levels observed using splenic DCs. Furthermore, IL-12 administration preferentially increased hepatic T cell activation and IFNγ expression in the RENCA mouse model of renal cell carcinoma. Collectively, the data shows systemic IL-12 administration enables hepatic DCs to overcome at least some aspects of the inherently suppressive milieu of the hepatic environment that could have important implications for the design of IL-12-based immunotherapeutic strategies targeting hepatic malignancies and infections.
authors.affiliation: Laboratory of Experimental Immunology, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, United States of America.
authors.forename: Tim
authors.initials: T
authors.lastname: Chan
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Back
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Subleski
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Weiss
authors.forename: John R
authors.initials: JR
authors.lastname: Ortaldo
authors.forename: Robert H
authors.initials: RH
authors.lastname: Wiltrout
mesh_terms: D000818:Animals; D002292:Carcinoma, Renal Cell / Q000276:immunology*; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000008:administration & dosage / Q000494:pharmacology*; D008099:Liver / Q000166:cytology / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018709:Statistics, Nonparametric; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D018664:Interleukin-12; D007371:Interferon-gamma