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Abstract

Cell-cell adhesion is critical for the generation of effective immune responses and is dependent upon the expression of a variety of cell surface receptors. Intercellular adhesion molecule-1 (ICAM- 1; CD54) is an inducible cell surface glycoprotein expressed at a low level on a wide range of cell types. Although its expression is dramatically increased at sites of inflammation, providing important means of regulating cell-cell interactions and thereby inflammatory responses, the intracellular regulatory elements and signaling pathways underlying the inducible expression of ICAM- 1 by proinflammatory cytokines were previously largely unknown. In this thesis, a novel posttranscriptional regulation of ICAM-1 gene expression by two proinflammatory mediators, interferon-γ (IFN-γ) and phorbol myristate acetate (PMA), and the possible role of serine/threonine (ser/thr) phosphorylation pathway in cycloheximide induced ICAM-1 message stabilization were investigated. The results show that (1) constitutively expressed ICAM-1 mRNA has a short half-life; (2) IFN-γ and PMA induce the accumulation of ICAM-1 message, at least in part, by stabilizing the mRNA; (3) the WN-γ responsive element(s) is located within the protein coding region encoding the cytoplasmic domain; (4) the PMA-responsive elements lie within the 3’ untranslated region (UTR) and may even be the AUUUA multimers; (5) cycloheximide, a potent eukaryotic protein synthesis inhibitor that superinduces the expression of many genes by preventing the degradation of otherwise labile mRNAs, also induces the level of ICAM- 1 mRNA by message stabilization; (6) the stabilizing effect of cycloheximide does not depend on the 3’UTR containing the AUUUA sequences; (7) the stabilization of ICAM-1 mRNA by cycloheximide is independent of its translational inhibition; and (8) the ser/thr phosphorylation pathway seems to play a crucial role in the cycloheximide-induced stabilization of ICAM- 1 message. These results demonstrate the existence of distinct destabilizing elements throughout the ICAM- 1 message that are responsive to the actions of various proinflammatory cytokines, and underscore the importance of posttranscriptional regulation of ICAM-1 expression during an inflammatory response.