DIFFERENTIAL REGULATION OF INTERLEUKIN-8 AND INTERCELLULAR-ADHESION MOLECULE-1 BY H2O2 AND TUMOR-NECROSIS-FACTOR-ALPHA IN ENDOTHELIAL AND EPITHELIAL-CELLS

The reactive oxygen intermediate H2O2 can function as a signaling mole cule to activate gene expression. In this study, we demonstrate that o xidant stress induced by tumor necrosis factor alpha (TNF alpha) or H2 O2 differentially regulates intercellular adhesion molecule-1 (ICAM-1) and interleukin-8 (IL-8) gene expression in endothelial and epithelia l cells. Northern blot analysis revealed that TNF alpha induced both I CAM-1 and IL-8 expression in either the A549 lung epithelial cell line or the human microvessel endothelial cell line (HMEC-1). In contrast, H2O2 selectively induced only ICAM-1 in HMEC-1 and only IL-8 in A549. This cell type-specific pattern of IL-8 expression was also observed in several other endothelial and epithelial cells. TNF alpha induced g reater IL-8 gene expression as compared with H2O2, but the kinetics of induction were similar. The induction of epithelial IL-8 message was accompanied by a corresponding increase in functional IL-8 protein sec retion as determined by a neutrophil motility assay. The increased neu trophil motility stimulated by conditioned media from H2O2- or TNF alp ha-exposed A549 cells was completely inhibited by an anti-IL-8 antibod y. TNF alpha and H2O2 also induced a differential pattern of CC chemok ine expression in A549. While TNF alpha induced both RANTES and MCP-1, H2O2 induced only MCP-1. These data suggest that epithelial cells und er oxidant stress contribute to the inflammatory cytokine network by s elective production of IL-8, MCP-1, and RANTES, which may critically i nfluence the site-specific recruitment of leukocyte subsets.