Whittall, John Trevor Douglas; (1992) Macrophage activation by interleukin 4. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Macrophages are cells of the immune system which have an important role in killing of micro-organisms, in the presentation of foreign antigen to other immune cells and in regulation of the immune system. There is also evidence that some macrophages can effect tumour cell lysis, whereas other cells from the same lineage may have nutritive functions. The control of many of these functions depends on responses of macrophages to cytokines and to bacterial products. In this study the principal aim has been to investigate the effect of one of these cytokines, Interleukin-4 (IL-4), on a number of the functions of murine macrophages and to compare this with the effects of another cytokine, Interferon-γ (IFN-γ) and a bacterial cell wall component, Lipopolysaccharide (LPS). The first part of the work is concerned with a series of experiments in which Interleukin-4 was identified as the active principle in a supernatant from activated T-cells which was able to activate a tumouricidal function of macrophages. Changes in macrophage expression of factors which may be relevant to their cytocidal functions were then studied. The effectors considered were secreted and membrane bound forms of Tumour Necrosis Factor (TNF)/ the reactive oxygen species (peroxide and superoxide) and reactive nitrogen intermediates (nitrite and nitric oxide). Significant changes in expression of TNF and superoxide were detected after IL-4 treatment of macrophages, which differed from those produced by IFN-γ and LPS. The influence of macrophage activating factors on the regulatory role of macrophages was investigated by studying macrophage-derived cytokines and molecules on the surface of macrophages which are involved in their communication with other cells. In addition to TNF, the cytokines assayed were Interleukin-1 (IL-1) and Interleukin-6 (IL-6). The expression of the leucocyte integrins CR3 and LFA-1 was also studied as they are important surface molecules in cell-cell interactions. Changes were observed in expression of these molecules after activation by IL-4 which were distinct from those observed with IFN-γ and LPS. The possible effect of IL-4 on presentation of antigen by macrophages was then investigated, by studying the level of expression of class I and class II major histocompatibility complex (MHC) molecules. The changes which were observed indicated that macrophage activation by IL-4 or IFN-γ increased MHC expression and that IFN-γ was more potent than IL-4 in promoting expression of MHC class II. It was also demonstrated that changes occurred in the level of expression of immunoglobulin receptors after activation by IL-4. In particular, expression of Immunoglobulin E receptors was increased by IL-4, whereas IFN-γ had no effect. In contrast there was no effect of IL-4 on expression of IgG receptors, which was increased by IFN-γ. The differences which were observed between IL-4 and IFN-γ in their effects on macrophages contributed to the main conclusions of this work. These were that macrophage activation by IL-4 differed from that by IFN-γ and that the role of IL-4 in macrophage biology may not be confined to tumour killing. The data suggested that IL-4 could also influence responses to antigens which have been opsonised by IgE antibody, antigen presentation and macrophage-mediated killing of micro-organisms.

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