Expression and regulation of ICAM-1 and VCAM-1 in streptococcal-cell-wall-induced hepatic granuloma
AdvisorYocum, David E.
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PublisherThe University of Arizona.
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AbstractHepatic granulomas are induced by a single intraperitoneal injection of streptococcal cell wall (SCW) into female Lewis rats. This inflammatory response has a biphasic course with an early accumulation of polymorphonuclear leukocytes in the liver followed by infiltration of mononuclear phagocytes. The expression of adhesion molecules may contribute to the recruitment of leukocytes to the liver. Therefore, in this study I investigated the expression and regulation of intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) on liver endothelial cells in a SCW rat model and in primary endothelial cell cultures treated with cytokines IL-1β, IL-6, IFN-γ, TNF-α and lipopolysaccharide (LPS). Immunohistochemical staining demonstrated that ICAM-1 was constitutively expressed on sinusoidal lining cells. Enhanced ICAM-1 expression was observed 3, 14 and 28 days after SCW injection. There was a gradation of ICAM-1 staining intensity with the strongest staining in periportal area. In primary endothelial cell culture, cells up-regulated surface ICAM-1 expression in response to cytokines in the following order: IL-1β + IFN-γ + TNF-α > IFN-γ + TNF-α > TNF-α + IL-1β or IFN-γ + IL-1β > TNF-α >IFN-γ > IL-1β. ICAM-1 was also up-regulated by LPS. Cytokine and LPS activated liver endothelial cells also increased ICAM-1 mRNA expression. The induction profile of ICAM-1 mRNA was identical to the profile of ICAM-1 expression on the cell surface. This parallel suggests that the increased surface ICAM-1 expression is associated with the increased ICAM-1 mRNA level. Interestingly, IL-6 had no effect on either surface ICAM-1 or mRNA production. Primary endothelial cell culture constitutively expressed both 7 domain (3.7 kb) and 3 domain (1.6 kb) VCAM-1 mRNAs. IL-1β, IL-6 and IFN-γ did not significantly affect VCAM-1 mRNA expression. TNF-α and LPS up-regulated 7 domain mRNA level 6 and 10 fold respectively with no effects on 3 domain mRNA expression. The most striking affects were induced by IFN-γ + TNF-α. This study suggests that the expression of ICAM-1 and VCAM-1 on liver endothelial cells could play an important role in the recruitment of leukocytes into the liver during SCW-induced hepatic inflammation. TNF-α was found to be produced by endothelial cells and may be one of the reasons for the chronicity of this lesion.
Degree ProgramGraduate College
Microbiology and Immunology