title: TGF-beta differentially modulates epidermal growth factor-mediated increases in leukemia-inhibitory factor, IL-6, IL-1 alpha, and IL-1 beta in human thymic epithelial cells.
abstract: The regulation of cytokine production by thymic epithelial cells (TEC) in the thymus is under coordinated and temporal control and is important for the development of T cells. Human TEC express TGF-beta R and epidermal growth factor (EGF) receptor, and produce TGF-beta 3 in vitro and in vivo. Furthermore, EGF has been shown to increase IL-1 alpha, IL-1 beta, IL-6 mRNA and protein levels in human TEC. Since EGF has been shown to modulate TGF-beta effector functions, we determined whether TGF-beta can modulate EGF-mediated increases in cytokine gene expression in human TEC. We established that a single TEC expresses both EGF receptor and TGF-beta R. TGF-beta plus EGF synergistically increased leukemia-inhibitory factor (LIF), additively increased IL-6, but had little effect on IL-1 alpha and IL-1 beta mRNA levels. In contrast, TGF-beta alone increased LIF and IL-6, had little effect on IL-1 alpha, and slightly decreased IL-1 beta mRNA levels. The increases in LIF and IL-6 mRNA levels by TGF-beta plus EGF correlate with the increases in LIF and IL-6 concentrations in TEC culture supernatants as detected by ELISA. We also determined the mechanism responsible for the increases in cytokine mRNA levels. TGF-beta plus EGF did not affect transcription of LIF and IL-6 genes; this suggests that the increases in the steady state levels of cytokine mRNA were mediated post-transcriptionally, most likely at the level of mRNA stability. Our data demonstrate that TGF-beta modulates TEC cytokine production. We speculate that TGF-beta produced in situ plays a role in thymocyte development by directly affecting thymocyte differentiation and by indirectly modulating TEC cytokine production.
authors.affiliation: Department of Cell Biology, Neurobiology, and Anatomy, Loyola University Stritch School of Medicine, Maywood, IL 60153, USA.
authors.forename: K S
authors.initials: KS
authors.lastname: Schluns
authors.forename: J E
authors.initials: JE
authors.lastname: Cook
authors.forename: P T
authors.initials: PT
authors.lastname: Le
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D002474:Cell-Free System / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004357:Drug Synergism; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D004847:Epithelial Cells; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D066246:ErbB Receptors / Q000096:biosynthesis; D006131:Growth Inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D000276:Adjuvants, Immunologic; D006131:Growth Inhibitors; D007375:Interleukin-1; D015850:Interleukin-6; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D004815:Epidermal Growth Factor; D066246:ErbB Receptors