Molecular mechanisms of LPS-induced activation of human monocytes/macrophages: molecular biological studies on functions of mono-ADP-ribosyltransferases ART3 and ART4

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Interaction of human monocytes/macrophages with lipopolysaccharides (LPS), the major outer membrane components of gram-negative bacteria, results in multiple intracellular biochemical modifications that can lead to severe pathophysiological reactions. We have previously shown that LPS induces the mRNA expression of mono-ADP-ribosyltransferase (ART) 3 and 4 and that a 31 kDa protein becomes ADP-ribosylated in response to LPS. ART3/ART4 belong to the family of ARTs which in humans consists of four members (ART1, 3-5). As ARTs are ectoenzymes that catalyze the transfer of ADP-ribose from NAD+ to an acceptor protein thereby modifying its function, ART3/ART4 could well contribute to such functional alterations. So far enzyme activity has only been demonstrated for ART1 and ART5 but not for ART3 and ART4. Molecular biological methods will be used to test whether enzyme activity of ART3/ART4 can be restored and whether ART3/ART4 have gained functional properties that facilitate cell-cell contact by interacting with other surface molecules. As the transcriptional level of ART3/ART4 in activated monocytes/macrophages is extremely low, tissues expressing those mRNA’s at higher levels will be included in the functional studies.