title: Elevated interleukin-27 levels in human neonatal macrophages regulate indoleamine dioxygenase in a STAT-1 and STAT-3-dependent manner.
abstract: Microbial infections are a major cause of infant mortality as a result of limitations in immune defences. Interleukin-27 (IL-27) is a heterodimeric cytokine produced primarily by leucocytes and is immunosuppressive toward lymphocytes and leucocytes. Our laboratory demonstrated that human neonatal macrophages express IL-27 more abundantly than adult macrophages. Similarly in mice, IL-27 expression is elevated early in life and maintained through infancy. To determine IL-27-regulated mechanisms that may limit immunity, we evaluated the expression of a number of genes in response to this cytokine in primary human neonatal macrophages. Indoleamine 2,3-dioxygenase (IDO) gene expression was increased dose-responsively by IL-27. We have previously demonstrated inhibition of T-cell proliferation and cytokine production by neonatal macrophage-generated IL-27, and IDO is often implicated in this negative regulation. An increase in IDO protein was demonstrated by immunofluorescence microscopy and was consistent with increased enzyme activity following treatment with IL-27. Inclusion of a soluble receptor to neutralize endogenous IL-27, decreased IDO expression and activity compared with untreated macrophages. In response to IL-27, neonatal macrophages phosphorylate signal transdcuer and activator of transcription 1 (STAT-1) and STAT-3. Both transcription factors are recruited to the IDO regulatory region. STAT-3 dominates during steady-state regulation by lower levels of endogenous IL-27 production. A shift to enhanced STAT-1 recruitment occurs during increased levels of exogenously supplied IL-27. These data suggest an interesting interplay of STAT-1 and STAT-3 to regulate IDO activity and immunosuppression in response to different levels of IL-27 in the microenvironment of the immune response that may further our understanding of this interesting cytokine.
authors.affiliation: Department of Biology, Briar Cliff University, Sioux City, IA, USA.
authors.forename: Joo-Yong
authors.initials: JY
authors.lastname: Jung
authors.affiliation: Biomedical Sciences Department, West Virginia School of Osteopathic Medicine, Lewisburg, WV, USA.
authors.forename: Madeline
authors.initials: M
authors.lastname: Gleave Parson
authors.affiliation: Department of Pathology Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, USA.
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Kraft
authors.affiliation: Biomedical Sciences Department, West Virginia School of Osteopathic Medicine, Lewisburg, WV, USA.
authors.forename: Logan
authors.initials: L
authors.lastname: Lyda
authors.affiliation: Biomedical Sciences Department, West Virginia School of Osteopathic Medicine, Lewisburg, WV, USA.
authors.forename: Brianna
authors.initials: B
authors.lastname: Kobe
authors.affiliation: Department of Biological Sciences, University of South Carolina, Columbia, SC, USA.|Center for Colon Cancer Research, University of South Carolina, Columbia, SC, USA.
authors.forename: Celestia
authors.initials: C
authors.lastname: Davis
authors.affiliation: Department of Pathology Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, USA.
authors.forename: Jembber
authors.initials: J
authors.lastname: Robinson
authors.affiliation: Department of Biological Sciences, University of South Carolina, Columbia, SC, USA.|Center for Colon Cancer Research, University of South Carolina, Columbia, SC, USA.
authors.forename: Maria Marjorette O
authors.initials: MM
authors.lastname: Peña
authors.affiliation: Biomedical Sciences Department, West Virginia School of Osteopathic Medicine, Lewisburg, WV, USA.
authors.forename: Cory M
authors.initials: CM
authors.lastname: Robinson
mesh_terms: D000328:Adult; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism; D007231:Infant, Newborn; D064094:Interleukin-27 / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D064094:Interleukin-27; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor
keywords: cytokines; gene regulation; human; signal transduction; transcription factors