an-Jie Li

Interferon γ-dependent Induction of Human Intercellular Adhesion Molecule-1 Gene Expression Involves Activation of a Distinct STAT Protein Complex

In response to interferon γ (IFNγ), intercellular adhesion molecule-1 (ICAM-1) is expressed on human keratinocytes, a cell type that is critically involved in cutaneous inflammation. An ICAM-1 5′ regulatory region palindromic response element, pIγRE, has been shown to confer IFNγ-dependent transcription enhancement. By electrophoretic mobility shift assays (EMSA), pIγRE forms a distinct complex with proteins from IFNγ-treated human keratinocytes, termed γ response factor (GRF). Binding of GRF is tyrosine phosphorylation-dependent, and mutations of pIγRE that disrupt the palindromic sequence or alter its spatial relationship abrogate GRF binding. Supershift EMSAs using antibodies to characterized STAT proteins suggest that GRF contains a Stat1α-like protein; however, non-ICAM-1 IFNγ-responsive elements (REs) known to bind Stat1α homodimers fail to compete for GRF binding in EMSA, and pIγRE does not cross-compete with these REs that complex with homodimeric stat1α. The pIγRE·GRF complex also displays a distinctly different electrophoretic mobility compared to that of IFNγREs complexed to homodimeric Stat1α. These findings indicate that a distinct complex containing a Stat1α-like protein mediates IFNγ-induced ICAM-1 gene transcription and identifies a subset of IFNγ-responsive genes that appear to be regulated by this complex.

The regulation of cell adhesion molecule gene expression.

Our current understanding of the regulation of expression of the genes encoding various leukocyte adhesion molecules, and in particular their expression by specific cellular components of the skin, reflects in many ways our understanding of gene regulation in general. The questions that may be addressed with respect to particular adhesion molecule genes are in essence individual examples of the fundamental questions of biology: how, when and why do cells do what they do? Whether a biologist is primarily concerned with growth, differentiation, development, homeostasis, oncogenesis, immune or inflammatory responses, or any other aspect of normal or abnormal cell behavior, that behavior can be viewed as entailing two global, closely interrelated, biologic events: a signaling mechanism to or within the cell that commands a response, and differential gene expression that constitutes the response. Throughout the life of any organism, these events, in one form or another, are continuously occurring and recurring in various tissues to varying degrees. Leukocyte cell adhesion molecules play vital roles in the trafficking and localization of leukocyte subsets, and their rapid and exquisitely choreographed expression dictates in part the nature and extent of an inflammatory or immunologic response at particular sites of injury or threat (1-10, 21). As detailed in the accompanying article by Lawley et al., specific adhesion molecules, particularly those expressed by microvascular endothelial cells of