Regulation of proto-oncogenes and immune system genes during CSF-1-induced macrophage differentiation
Ghildyal, Namit
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https://hdl.handle.net/2142/19167
Description
Title
Regulation of proto-oncogenes and immune system genes during CSF-1-induced macrophage differentiation
Author(s)
Ghildyal, Namit
Issue Date
1990
Doctoral Committee Chair(s)
Schook, Lawrence B.
Department of Study
Animal Science
Discipline
Animal Science
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Biology, Molecular
Health Sciences, Immunology
Language
eng
Abstract
CSF-1-induced bone marrow-derived macrophage (BMDM) differentiating in vitro acquire both antigen presenting and tumoricidal capabilities. In order to understand the molecular origin of macrophage diversity transcriptional and post-transcriptional regulation of genes involved in affector and effector functions were studied. Transcripts of c-fms and c-fos were detected at all stages of differentiation, whereas c-myc gene expression was highest during the proliferative stages of development. Endotoxin treatment of BMDM enhanced the expression of all proto-oncogenes, however the c-myc mRNA levels were highest on day 3 of culture. IFN-$\gamma$ treatment of BMDM cultures also enhanced the transcription of proto-oncogenes. Thus, it is felt that c-fms, c-fos and c-myc may be related to the complex mechanism of macrophage activation as evidenced by the stage-specific gene regulation. Interesting observations were made on the study of genes involved with functional state macrophage. Transcription of MHC class I and II genes occurred in the absence of any known Ia-inducing factor and the transcripts reached a maximum (3- to 4-fold) between days 5-7 of culture. IFN-$\gamma$ enhanced the transcription of both class I (2- to 5-fold) and II (2- to 10-fold) genes. Nuclear run-off assay results demonstrated that endotoxin treatment of the BMDM cultures augmented expression of both class I (2- to 3-fold) and II (2- to 3-fold) genes suggesting a post-transcriptional control of the MHC genes in the absence of an Ia-inducing factor. Upon endotoxin stimulation, transcription of IL-1$\alpha$ and IL-1$\beta$ showed almost similar kinetics which paralleled the kinetics of accumulation of steady state mRNA. This suggested that the expression of IL-1 genes are regulated transcriptionally. Tough both IFN-$\gamma$ and endotoxin enhanced (4- to 5-fold) the transcription of TNF-$\alpha$ gene, endotoxin had a more pronounced effect. The kinetics of TNF-$\alpha$ transcription paralleled the kinetics of steady state TNF-$\alpha$ mRNA accumulation, thereby suggesting both transcriptional and post-transcriptional control in the expression of TNF-$\alpha$ gene. Thus, these findings indicate that during macrophage development there is a sequential expression of immune system genes which is intrinsically determined.
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