The purpose of the proposed study is to establish structural relationships between human macrophage directed lymphokines and to elucidate the mechanism of action of MIF. The lymphokines to be examined are migration inhibitory factor (MIF), the macrophage activating factor which induces the elimination of virus in human macrophages (antiviral MAF) which is not identical with interferon-gamma, the macrophage activating factor which induces the killing of Leishmania parasites n macrophages (anti-leish-mania-MAF) and the macrophage activating factor which induces tumor cell killing (anti-tumor-MAF). Furthermore, the structural differences underlying the different first and second day MIF species established by us in earlier studies will be determined. Structural comparisons will also be made between macrophage directed lymphokines and the well characterized lymphokine interferon-gamma. The planned approach is, first to purify to homogeneity the various lymphokine species from the supernatants of T-T cell hybrids. We will then attempt to structurally define and compare the purified lymphokine species by sensitive analytical techniques such as peptide mapping and sequencing. Recent studies on interferon-gamma indicate that different interferon-gamma variants are generated by postranscriptional and/or posttranslational modifications of a single translation product. We will, therefore, analyze the various MIF species, anti-viral MAF, anti-leishmania MAF and finally, anti-tumor MAF to determine whether they share significant amounts of common primary structure which would indicate modification of a common precursor. If we find common strutural elements among these lymphokines, we will compare it with the structure of a putative precursor. The other main objective is the understanding of the mechanism of the MIF-action. We will investigate the role of such potentially important cell surface components as thrombospondin and laminin, extracellular glycoproteins found on the surface of a number of cells in the response of the macrophage to MIF.
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