ICAM-1-INDEPENDENT LYMPHOCYTE TRANSMIGRATION ACROSS HIGH ENDOTHELIUM - DIFFERENTIAL UP-REGULATION BY INTERFERON-GAMMA, TUMOR-NECROSIS-FACTOR-ALPHA AND INTERLEUKIN-1-BETA

The adhesion of lymphocytes to cytokine-treated high endothelium was studied using cultured high endothelial cells (HEC). Pretreatment of the HEC layer with a variety of cytokines caused up-regulation of lymphocyte adhesion with the effects ordered interferon-gamma (IFN-gamma) > tumor necrosis factor alpha (TNF-alpha) greater-than-or-equal-to interleukin 1-beta (IL 1-beta). Increased lymphocyte adhesion was found to be independent of ICAM-1 as expression by HEC was not increased by cytokines and antibodies against ICAM-1 did not block adhesion. The peptide CS1 and anti-beta(1) integrin subunit antibodies, however, caused partial inhibition of lymphocyte adhesion thus indicating a role for fibronectin on HEC and alpha(4)beta(1) on lymphocytes. Study of the kinetics of lymphocyte adhesion showed that the effects of IFN-gamma and TNF-alpha were persistent and remained detectable 2.5 h after removal of the cytokines whereas the effects of IL 1-beta were transient and were not sustained beyond 1 h. All of the cytokines used caused transient increases in the number of surface-bound lymphocytes with IFN-gamma > TNF-alpha greater-than-or-equal-to IL 1-beta, however, the most dramatic effect was on the transmigration of lymphocytes across the HEC. Both IFN-gamma and TNF-alpha caused sustained increased transmigration with IFN-gamma having the greater effect. IL 1-beta had little effect on transmigration. This model demonstrates that the binding and transmigration of lymphocytes across HEC can be differentially regulated by the actions of individual cytokines. These results support the concept that locally produced cytokines regulate HEC function within the lymph node.