Integrin regulation of an inflammatory effector gene. Direct induction of the tissue factor promoter by engagement of beta 1 or alpha 4 integrin chains.

Abstract

Inflammatory genes are regulated in cells of monocyte (Mo) lineage by a variety of cellular encounters, including adhesion mediated by integrins. The role of the beta 1 family of integrins in the direct induction 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 members of the beta 2 integrin family, with specific mAbs as surrogate ligands immediately and directly induced high level surface expression of TF, and accumulation of TF mRNA, as well as production of TNF-alpha and HIV-1 virus. The mechanism responsible for induction of TF gene transcription mediated by the engagement of alpha 4 or beta 1 was elucidated 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), which contained two AP-1 sites as well as a single kappa B-like site. Mutation of either the AP-1 sites or kappa B-like site greatly diminished responsiveness to integrin engagement. This InRE also conferred responsiveness to a heterologous promoter in the same reporter plasmid. Binding of mAbs to either alpha 4 or beta 1 led to nuclear translocation of 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 engagement. These studies expand knowledge of integrin regulation of immediate early gene expression in Mo and molecular encounters that are inferred to play an active role in Mo effector functions.