title: Aberrant regulation of IL-1 expression in macrophages from young autoimmune-prone mice.
abstract: IL-1 is a multifunctional, immunoregulatory polypeptide produced by many cell types. Because activated macrophages are a major source of IL-1 and have also been implicated in the pathogenesis of autoimmune disease, we investigated the regulation of IL-1 expression in several autoimmune-prone strains of mice. Peritoneal macrophages derived from the autoimmune-prone strains MRL/lpr, MRL/+, NZB, and NZB/W F1, as well as NZW, displayed transient expression of IL-1 in contrast to the stable expression characteristic of control normal strains including A. Thy, A/J, B10, B10.A, B10.D2, C57BL/6, BALB/c, and C3H/HeN. The down-regulation of IL-1 by macrophages from the autoimmune-prone mice was not attributable to inherently defective signal transduction because macrophages from both the normal and autoimmune-prone strains displayed substantial initial levels of cell-associated and secreted IL-1. However, during the first 2 to 3 days in culture, macrophages from autoimmune-prone mice became progressively refractory to both induction and maintenance of IL-1, a pattern that correlated with changes in the levels of IL-1 alpha and beta mRNA. The progressive reduction in IL-1 expression by macrophages from these autoimmune-prone strains was not due to a reduction in general metabolism or viability, because expression of cell surface antigens, including MHC class I and II Ag and LFA-1, was comparable to that of control macrophages. Because IL-1 plays a critical role in the homeostasis of a variety of cell lineages, defective expression, and maintenance of IL-1 (and perhaps other cytokines) by macrophages from the autoimmune-prone strains may contribute to the immune dysregulation that develops in these mice. Alternatively, cytokine dysregulation might not contribute directly to disease, but rather reflect a more basic defect related to specific signal transducing or gene regulatory pathways.
authors.affiliation: Laboratory of Immunology, Evans Memorial Department of Clinical Research, University Hospital, Boston, MA 02118.
authors.forename: R P
authors.initials: RP
authors.lastname: Donnelly
authors.forename: J
authors.initials: J
authors.lastname: Levine
authors.forename: D Q
authors.initials: DQ
authors.lastname: Hartwell
authors.forename: G
authors.initials: G
authors.lastname: Frendl
authors.forename: M J
authors.initials: MJ
authors.lastname: Fenton
authors.forename: D I
authors.initials: DI
authors.lastname: Beller
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000209:etiology / Q000276:immunology*; D001853:Bone Marrow / Q000276:immunology; D002478:Cells, Cultured; D015536:Down-Regulation; D007375:Interleukin-1 / Q000032:analysis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008232:Lymphoproliferative Disorders / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha