The major thrust of our research during the last several years has been the detailed characterization of novel """"""""interferon"""""""" mRNA species induced by poly(I) poly (C) in diploid human fibroblasts: a 1.3 kb """"""""interferon-beta2"""""""" species and a 1.8 kb """"""""interferon-beta3"""""""" species. The cytokine, to which we originally applied the name """"""""interferon-beta2"""""""" and which is now called """"""""interleukin-6,"""""""" has emerged as a major systemic alarm signal produced in response to tissue injury. IL-6 phosphoglycoproteins (size range 23-30 kDa) in turn affect the function of a wide variety of different cell types. IL-6 elicits major changes in the biochemical, physiological and immunological status of the host (e.g. the """"""""acute phase"""""""" response.) We have developed a broad research program which has already provided key insights into the structure and function of human IL-6. We propose to continue this effort in the following areas: I. MOLECULAR BIOLOGY: The hallmark of IL-6 gene regulation is the induction of the gene in many different tissues by inflammation-association cytokines (IL-1), TNF, PDGF, other IFNs). We plan to conduct detailed investigations of the following: cis-acting regulatory DNA elements in the IL-6 promoter and trans-acting wild-type and mutant transcription factors involved in the regulation of this gene, particularly focusing on the 23-bp MRE identified by us; tissue-specificity of IL-6 induction and the molecular events that lead to constitutive vs. inducible expression of IL- 6. II. BIOCHEMISTRY: Different tissues secrete multiple forms of IL-6 which are post-translationally modified. We plan to characterize these modifications; characterize the biochemical nature of IL-6 in human body fluids (particularly the 45 kDa IL-6 complex) and carry out structure- activity studies of natural and recombinant IL-6 proteins. III. CELL BIOLOGY: IL-6 regulates expression of specific genes in several different target, cells. We propose to explore the effects of IL-6, alone and in combination with IL-1, TNF and IFN-gamma, on plasma protein secretion by hepatocytes, monocytes and fibroblasts; characterize the novel IL-6 """"""""receptor"""""""" mRNA species found in fibroblasts and investigate the inhibition of epithelial cell proliferation by IL-6. IV. PATHOPHYSIOLOGY: High IL-6 levels are found in plasma and body fluids in acute inflammatory disease states. We shall investigates the significance of altered IL-6 levels (systemic and local) in patients with acute and chronic infections, neoplasia and autoimmune diseases; and explore the association between IL-6 haplotypes and specific disease states.
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