Characterization of the CD11a (alpha L, LFA-1 alpha) integrin gene promoter

Abstract

Human lymphocyte function-associated antigen-1 (LFA-1, CD11a/CD18, alpha L/beta 2) is a cell surface heterodimer, which, together with Mac-1 (CD11b/CD18, alpha M/beta 2) and p150,95 (CD11c/CD18, alpha X/beta 2), constitutes the leukocyte integrin beta 2 (CD18) subfamily. LFA-1 is the only integrin expressed on all leukocyte lineages and functions both as a key adhesion receptor in immune and inflammatory processes and as a signal-transducing molecule. To elucidate the molecular basis for the leukocyte-restricted expression of LFA-1, the promoter region of the CD11a gene has been isolated and functionally characterized. The 5' region of the CD11a gene exhibits a similar exon/intron organization as the CD11b, CD11c, and VLA-2 alpha genes but is different from that of the genes encoding VLA-4 alpha, VLA-5 alpha, and gpIIb. Several tightly clustered transcription initiation sites have been identified on the CD11a gene, with the major site resembling the "initiator" sequence. Transient expression of CD11a promoter-based reporter gene constructs in both LFA1+ and LFA1- cell lines demonstrated that the fragment spanning from -880 to +83 is involved in the tissue-specific expression of LFA-1. Functional analysis of different fragments within the -880/+83 fragment suggested the presence of negative regulatory elements between -880 and -226 and demonstrated that the proximal region of the CD11a gene promoter exhibits tissue-specific activity.