Regulation of ICAM-1-mediated fibroblast-T cell reciprocal interaction: implications for modulation of gut inflammation.
OBJECTIVE
Immune-nonimmune cell interactions modulate mucosal immunity. We investigated the expression of adhesion molecules by intestinal fibroblasts, the effect of immune cell-derived factor on fibroblast binding of T cells, and the consequences of interfering with adhesion molecule expression on fibroblast-T cell interaction.


METHODS
Expression of fibroblast intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 surface and messenger RNA (mRNA) was measured before and after exposure to immune cell-derived supernatants. Fibroblasts were treated with antibodies to ICAM-1 or VCAM-1, or ICAM-1 antisense oligonucleotide Isis 2302, before a T-cell adhesion assay.


RESULTS
Fibroblast activation by immune cell-derived cytokines enhanced ICAM-1 and VCAM-1 surface expression and mRNA as well as adhesiveness for T cells. Blockade with neutralizing antibodies showed that binding was almost exclusively dependent on ICAM-1. Isis 2302 specifically reduced fibroblast ICAM-1 mRNA and dose-dependently inhibited ICAM-1 surface expression and T-cell binding.


CONCLUSIONS
ICAM-1 is essential for intestinal fibroblast binding of T cells, a phenomenon that is efficiently and specifically disrupted by ICAM-1 antisense oligonucleotides. These observations emphasize the crucial regulatory role of fibroblasts in mucosal immunity and their potential as targets for therapeutic intervention in intestinal inflammation.
Musso
A
A
Division of Gastroenterology, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
Condon
T P
TP
West
G A
GA
De La Motte
C
C
Strong
S A
SA
Levine
A D
AD
Bennett
C F
CF
Fiocchi
C
C
D015152:Blotting, Northern; D002448:Cell Adhesion; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D005347:Fibroblasts / Q000276:immunology / Q000473:pathology*; D006801:Humans; D007249:Inflammation; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000502:physiology*; D007413:Intestinal Mucosa / Q000276:immunology* / Q000473:pathology*; D007963:Leukocytes, Mononuclear / Q000276:immunology; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger / Q000032:analysis; D013601:T-Lymphocytes / Q000502:physiology*; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000502:physiology
D017077:Culture Media, Conditioned; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1