CROSS-LINKING OF INTERCELLULAR-ADHESION MOLECULE-1 (CD54) INDUCES AP-1 ACTIVATION AND IL-1-BETA TRANSCRIPTION

Leukocytes adhere to target cells through their integrins and play a c rucial role in self-defense, inflammation, and differentiation, Interc ellular adhesion molecule-1 (ICAM-1;CD54) is a representative ligand f or integrins and is expressed on many cell types, some of which are ta rgets for leukocyte adhesion. Recent studies suggest that adhesion mol ecules function not only as a cellular glue, but also as a signal tran sducer. However, it remains to be clearly defined whether engagement o f ICAM-1 is able to induce activation signals in target cells. In rheu matoid synovium, synovial cells are known to express abundant ICAM-1 a nd produce multiple inflammatory cytokines, such as IL-1 beta. In this study, we provide the first evidence that ICAM-1 engagement induces a ctivation of the transcription factor AP-1 and transcription of the IL -1 beta gene using a specific Ab to cross-link ICAM-1 on a rheumatoid synovial cell line (Ell cells). This evidence includes ICAM-1 cross-li nking-dependent induction of 1) in situ IL-1 beta transcription and pr otein synthesis, 2) transiently transfected chloramphenicol acety(tran sferase (CAT) reporter plasmids containing both the IL-1 beta LPS-resp onsive enhancer (between -3134 and -2729) as well as multiple copies o f an AP-1 site from this enhancer (between -3117 and -3111), and 3) th e binding of a Jun/Fos family complex to this AP-1 site. Thus, ICAM-1 not only functions as a glue for integrin binding, but also as a trans ducer for AP-1 activation signals important for IL-1 beta gene transcr iption.