INTERLEUKIN-13 SELECTIVELY INDUCES MONOCYTE CHEMOATTRACTANT PROTEIN-1SYNTHESIS AND SECRETION BY HUMAN ENDOTHELIAL-CELLS - INVOLVEMENT OF IL-4R-ALPHA AND STAT6 PHOSPHORYLATION

Chemokines secreted by endothelium have been demonstrated to promote l eucocyte recruitment to sites of inflammation. In the present study we investigated the effect of the T lymphocyte-secreted cytokine interle ukin (IL)-13 on endothelial expression of chemokines. Employing in sit u hybridization and enzyme-linked immunosorbent assay (ELISA) techniqu es we demonstrate that IL-13, which shares many of its activities with IL-4, selectively induces expression of the C-C chemokine monocyte ch emoattractant protein (MCP)-1 in human umbilical vein endothelial cell s (HUVEC). However, it fails to up-regulate other C-C and C-X-C chemok ines potentially inducible in endothelium such as RANTES (regulated on activation, normal T expressed and secreted), gro-alpha, or IL-8. IL- 13 dose-dependently induces monocyte chemotactic activity by HUVEC whi ch can be efficiently blocked by neutralizing antisera against MCP-1. In contrast to the synergistic effect of IL-13 and tumour necrosis fac tor-alpha (TNF-alpha) on endothelial vascular cell adhesion molecule-1 (VCAM-1) surface expression, TNF-alpha-induced secretion of MCP-1 is not augmented by IL-13. Studying the signalling pathway activated by I L-13 it is demonstrated that a neutralizing monoclonal antibody (mAb) to the 140 000 MW component of the IL-4 receptor (IL-4R alpha) inhibit s the effect of IL-13. Immunoprecipitation studies reveal that endothe lial IL-4R alpha is rapidly tyrosine phosphorylated upon treatment wit h IL-13 and IL-4. We furthermore show that both cytokines activate the signal transducer and activator of transcription (Stat) protein-6 in endothelial cells. Our data suggest that IL-13 partly utilizes compone nts of the IL-4 receptor signalling pathway for induction of endotheli al MCP-1 expression to facilitate recruitment of blood leucocytes.