MODULATION OF ADHESION MOLECULE EXPRESSION ON ENDOTHELIAL-CELLS DURING THE LATE ASTHMATIC REACTION - ROLE OF MACROPHAGE-DERIVED TUMOR-NECROSIS-FACTOR-ALPHA

In a previous work we have demonstrated that in patients exhibiting a late allergic reaction (LAR), alveolar macrophages (AM) collected 18 h after bronchial allergen challenge produced high levels of IL-6 and t umour necrosis factor-alpha (TNF) which is known to up-regulate the en dothelial cell expression of adhesion molecules participating in the d evelopment of the inflammatory reaction in bronchial asthma. For these reasons, we evaluated the effect of AM supernatants from asthmatic pa tients developing an LAR on intercellular adhesion molecule-1 (ICAM-1) and endothelial leucocyte adhesion molecule-1 (ELAM-1) expression by human endothelial cells. The expression of adhesion molecules was asse ssed by an ELISA method and compared with the effect of an optimal dos e of human recombinant (hr) TNF. Results showed that AM supernatants, from challenged asthmatics developing an LAR, increased significantly the ICAM-1 and ELAM-1 expression on endothelial cells to a level simil ar to that obtained in the presence of hrTNF (500 U/ml) (P < 0.001 in both cases, respectively 90.4% and 75.2% of the level obtained with hr TNF). In contrast, AM supernatants from asthmatics at baseline or exhi biting, after challenge, a single early reaction bad no significant ef fect on these parameters (P=NS in both cases, respectively 23.5% and 2 4.7% of the ICAM-1 expression, 22.7% and 15.3% of the ELAM-1 expressio n obtained with hrTNF). AM-derived TNF present in these supernatants w as thought to play a key role in endothelial cell stimulation, since: (i) TNF concentration in AM supernatants correlated with its effect on ICAM-1 (r=0.80, p< 10(-4)) and ELAM-1 expression (r=0.88, P< 10(-5)); and (ii) a neutralizing anti-TNF antibody decreased their effect (68% and 80% respectively on ICAM-1 and ELAM-1 expression). Moreover, the role of IL-6 was excluded on the basis both of the hrIL-6 inefficiency to induce ICAM-1 and ELAM-1 synthesis, even in costimulation with hrT NF, and of anti-IL-6 antibody to neutralize the effect of AM supernata nts. Our results suggest that, beside mast cells and lymphocytes, macr ophages might participate in the induction of the local inflammatory r eaction observed in bronchial asthma. During the LAR, cytokines and es pecially TNF are able, through an enhanced adhesion molecule expressio n on endothelial cells, to facilitate the bronchial cellular influx.