INTEGRIN REGULATION OF AN INFLAMMATORY EFFECTOR GENE - DIRECT INDUCTION OF THE TISSUE FACTOR PROMOTER BY ENGAGEMENT OF BETA-1 OR ALPHA-4 INTEGRIN CHAINS

Inflammatory genes are regulated in cells of monocyte (Mo) lineage by a variety of cellular encounters, including adhesion mediated by integ rins. The role of the beta 1 family of integrins in the direct inducti on of immediate early gene expression was analyzed by using the tissue factor (TF) gene. Engagement of alpha 4 or beta 1 on Mo, but not memb ers of the beta 2 integrin family, with specific mAbs as surrogate lig ands immediately and directly induced high level surface expression of TF, and accumulation of TF mRNA, as well as production of TNF-alpha a nd HIV-1 virus. The mechanism responsible for induction of TF gene tra nscription mediated by the engagement of alpha 4 or beta 1 was elucida ted by using THP-1 monoblastic leukemia cells. Functional analysis of plasmids containing the TF promoter expressing the luciferase reporter gene identified a cis-acting integrin-responsive element (InRE), whic h contained two AP-1 sites as well as a single kappa B-like site. Muta tion of either the AP-1 sites or kappa B-like site greatly diminished responsiveness to integrin engagement. This InRE also conferred respon siveness to a heterologous promoter in the same reporter plasmid. Bind ing of mAbs to either alpha 4 or beta 1 led to nuclear translocation o f the c-Rel/p65 heterodimer that preferentially bound to the TF kappa B-like site, In contrast, constitutive binding of AP-1 proteins to the two AP-1 sites was not increased by alpha 4 or beta 1 integrin engage ment. These studies expand knowledge of integrin regulation of immedia te early gene expression in Mo and molecular encounters that are infer red to play an active role in Mo effector functions.