title: Development of functional diversity in mouse macrophages. Mutual exclusion of two phenotypic states.
abstract: The objective of this study was to investigate the mechanisms that contribute to the generation of macrophage functional diversity. Exposure of mouse bone marrow-derived macrophages to beta-1,3-glucan, a particulate inflammatory stimulus, or polyinosinate-polycytidylate (poly[I:C]), a stimulus of macrophage cytocidal activation, induced distinct and stimulus-specific patterns of gene expression. These changes were characterized by an up-regulation of the expression of the acid hydrolase beta-glucuronidase and platelet-derived growth factor B following incubation with beta-1,3-glucan and a stimulation of the expression of the complement component Bf, beta-interferon, and the reactive nitrogen intermediates NO2/NO3 during incubation with poly[I:C]. The induction of Bf expression by poly[I:C] could not be explained on the basis of distinct subpopulations of cells since in situ hybridization with a mouse Bf cRNA probe revealed a uniform and substantial increase in Bf expression by the entire population of cells. Incubation of macrophages with beta-1,3-glucan before stimulation with poly[I:C] was found to strongly attenuate the expression of Bf and beta-interferon. Conversely, incubation with poly[I:C] prior to exposure to beta-1,3-glucan substantially blocked the stimulation of beta-glucuronidase and platelet-derived growth factor B expression, indicating that these two responses were expressed in a mutually antagonistic fashion. However, after removal of either stimulus and following a period in which the primary response was allowed to decay, the cells regained their capacity to subsequently respond to either the same stimulus or to a different stimulus. Collectively, these findings indicate, first, that the heterogeneity of gene expression seen in response to poly[I:C] represents an adaptive response of the entire macrophage population rather than the restricted responses of distinct subpopulations of cells. Second, macrophages respond to these stimuli in a sequential fashion. These findings thus have a significant bearing on our understanding of the regulation of macrophage heterogeneity in host defense.
authors.affiliation: Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Denver, Colorado 80206.
authors.forename: D J
authors.initials: DJ
authors.lastname: Laszlo
authors.forename: P M
authors.initials: PM
authors.lastname: Henson
authors.forename: L K
authors.initials: LK
authors.lastname: Remigio
authors.forename: L
authors.initials: L
authors.lastname: Weinstein
authors.forename: C
authors.initials: C
authors.lastname: Sable
authors.forename: P W
authors.initials: PW
authors.lastname: Noble
authors.forename: D W
authors.initials: DW
authors.lastname: Riches
mesh_terms: D000818:Animals; D002469:Cell Separation; D002478:Cells, Cultured; D011415:Complement Factor B / Q000235:genetics; D005260:Female; D005936:Glucans / Q000494:pharmacology; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism; D016130:Immunophenotyping; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D009569:Nitric Oxide / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D047071:beta-Glucans
chemical_list: D005936:Glucans; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D047071:beta-Glucans; D009569:Nitric Oxide; D016899:Interferon-beta; C033363:beta-1,3-glucan; D005966:Glucuronidase; D011415:Complement Factor B; D011070:Poly I-C