Intercellular adhesion molecule-1 deficiency attenuates the development of skin fibrosis in tight-skin mice.

Abstract

The tight-skin (TSK/+) mouse, a genetic model for systemic sclerosis, develops cutaneous fibrosis. Although a fibrillin 1 gene mutation and immunological abnormalities have been demonstrated, the roles of adhesion molecules have not been investigated. To directly assess roles of adhesion molecules in skin fibrosis, TSK/+ mice lacking L-selectin and/or ICAM-1 were generated. The deficiency of ICAM-1, but not L-selectin, significantly suppressed ( approximately 48%) the development of skin sclerosis in TSK/+ mice. Similarly, ICAM-1 antisense oligonucleotides inhibited skin fibrosis in TSK/+ mice. Although T cell infiltration was modest into the skin of TSK/+ mice, ICAM-1 deficiency down-regulated this migration, which is consistent with the established roles of endothelial ICAM-1 in leukocyte infiltration. In addition, altered phenotype or function of skin fibroblasts was remarkable and dependent on ICAM-1 expression in TSK/+ mice. ICAM-1 expression was augmented on TSK/+ dermal fibroblasts stimulated with IL-4. Although growth or collagen synthesis of TSK/+ fibroblasts cultured with IL-4 was up-regulated, it was suppressed by the loss or blocking of ICAM-1. Collagen expression was dependent on the strain of fibroblasts, but not on the strain of cocultured T cells. Thus, our findings indicate that ICAM-1 expression contributes to the development of skin fibrosis in TSK/+ mice, especially via ICAM-1 expressed on skin fibroblasts.

• Authors: Yukiyo Matsushita, Minoru Hasegawa, Takashi Matsushita, Manabu Fujimoto, Mayuka Horikawa, Tomoyuki Fujita, Ayako Kawasuji, Fumihide Ogawa, Douglas A Steeber, Thomas F Tedder, Kazuhiko Takehara, Shinichi Sato
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 179 Issue 1 Pg. 698-707 (Jul 01 2007) ISSN: 0022-1767 [Print] United States
• PMID: 17579093 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• CD3 Complex
• Cytokines
• Transforming Growth Factor beta
• Intercellular Adhesion Molecule-1
• L-Selectin
• Collagen

Topics

• Animals
• CD3 Complex (biosynthesis)
• Cell Migration Inhibition
• Cells, Cultured
• Coculture Techniques
• Collagen (antagonists & inhibitors, biosynthesis, genetics)
• Cytokines (antagonists & inhibitors, biosynthesis, genetics)
• Down-Regulation (immunology)
• Female
• Fibroblasts (immunology, metabolism, pathology)
• Fibrosis
• Intercellular Adhesion Molecule-1 (biosynthesis, genetics, physiology)
• Intracellular Fluid (immunology, metabolism)
• L-Selectin (genetics, physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Skin (immunology, metabolism, pathology)
• T-Lymphocyte Subsets (immunology, metabolism, pathology)
• Th2 Cells (immunology, metabolism)
• Transforming Growth Factor beta (antagonists & inhibitors, biosynthesis, genetics)
• Up-Regulation (immunology)