REGULATORY ROLES OF TUMOR-NECROSIS-FACTOR-ALPHA AND INTERLEUKIN-1-BETA IN MONOCYTE CHEMOATTRACTANT PROTEIN-1-MEDIATED PULMONARY GRANULOMA-FORMATION IN THE RAT

Intravenous infusion of particulate yeast cell wall glucan into rats r esults in the synchronous development of angiocentric pulmonary, granu lomas that are composed almost entirely of monocytes and macrophages, Previous studies indicate that locally produced monocyte chemoattracta nt protein-1 (MCP-I) is required for full granuloma development. Becau se tumor necrosis factor-alpha (TNF-alpha) and interleukin 1 (IL-1) ca n induce MCP-1 production in a variety of cell types, we sought to det ermine their potential regulatory roles in this model. A single infusi on of anti-TNF-alpha antibody at the time of glucan infusion (time 0) markedly reduced MCP-1 mRNA levels at 1 and 6 hours but not at later t ime points; there was no effect on granuloma size or number measured a t 48 hours. When multiple infusions of anti-TNF-alpha antibody were ad ministered over a 23-hour period (0 to 23 hours), MCP-1 mRNA was reduc ed through 24 hours, there was a significant reduction in peak broncho alveolar lavage fluid MCP-1 activity at 48 hours, and there were marke d reductions in granuloma size and number at 48 hours, Similar results were observed in animals that received infusions of anti-IL-1 beta. I nfusion of anti-IL-1 beta at time 0 resulted in moderate reductions in MCP-1 mRNA at 1 and 6 hours and had no effect on granuloma size or nu mber measured at 48 hours. When multiple infusions of anti-IL-1 beta w ere administered over a 23-hour period CO to 23 hours), MCP-1 mRNA was reduced through 24 hours, there was a moderate reduction in peal bron choalveolar lavage fluid MCP-1 activity at 48 hours, and there were ma rked reductions in granuloma size and number at 48 hours. A single inf usion of anti-TNF-alpha and anti-IL-1 beta together at time 0 resulted in marked reductions in whole lung MCP-1 and mRNA at 1 and 6 hours, b ut not at 24 hours. Multiple combined infusions of anti-TNF-alpha and anti-IL-1 beta over a 23-hour period resulted in additive reductions i n MCP-1 mRNA through 24 hours, bronchoalveolar lavage fluid MCP-1 acti vity at 48 hours, and granuloma size and lumber at 48 hours. These dat a suggest that locally produced TNF-alpha and IL-1 beta play regulator y roles in glucan-induced pulmonary granulomatous vasculitis through t he modulation of local MCP-1 production.