Effects of 2,3,7,8-Tetrachlorodibenzo-p-dioxin on Leukocyte Function-associated Antigen-1 Mediated Splenocyte Adhesion

Abstract

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a widespread environmental contaminant that induces various types of immunotoxicity. One effect of exposure to this contaminant is alteration in cell adhesiveness. Leukocyte function-associated antigen-1 (LFA-1) plays an important role not only in T-cell recruitment into sites of inflammation and lymphoid tissues, but also in T-cell activation and in the development of specific immune responses. We, therefore, examined whether the alteration in cell adhesiveness is associated with the modulation of LFA-1 expression and its second messengers following exposure to TCDD. In vitro, 10 nM TCDD exposure suppressed splenocyte adhesion. In addition, the adhesiveness was reduced after in vivo exposure to TCDD (15 μg/kg) for six weeks with a one week interval and after additional in vitro stimulation with anti-CD3. The inhibition of adherence after TCDD exposure was related to a decreased expression of LFA-1, and expression patterns of Rap1 following TCDD exposure correlated with those of LFA-1 expression. However, TCDD did not selectively alter LFA-1 or Rap1 expression in T-cell subsets. TCDD caused apparent changes in PI 3-kinase expression levels and the expression patterns of H-Ras correlated with those of PI 3-kinase expression. These data suggest that TCDD exposure down-regulates the conformation and ligand binding affinity of LFA-1 by Rap1 and PI 3-kinase signaling pathways with the decreased expression of LFA-1, and consequently leads to a decrease in the LFA-1-mediated adhesion.