MONOCYTE CHEMOATTRACTANT PROTEIN-1 SYNTHESIS BY MURINE LUNG FIBROBLASTS MODULATES CD4(-CELL ACTIVATION() T)

This study addressed the role of endogenous monocyte chemoattractant p rotein-1 (MCP-1) in Ag-stimulated lymphokine synthesis and proliferati on by CD4(+) T cells during their coculture with purified lung fibrobl asts or splenic macrophages. Initial experiments showed that fibroblas ts exposed to IL-4, TNF alpha, or IL-4 and TNF-alpha (all at 10 ng/ml) for 24 h released five- to eightfold more MCP-1 than similarly treate d splenic macrophages. In 72-h coculture experiments, the synthesis of IL-4 by OVA-activated CD4(+) T cells added to lung fibroblasts or spl enic macrophages was significantly inhibited when endogenous MCP-1 was neutralized using polyclonal anti-MCP-1 antiserum. In these same cocu ltures, IFN-gamma levels were significantly enhanced. Similarly, IFN-g amma levels were significantly enhanced in 72-h cocultures of a purifi ed peptide derivative-activated CD4(+) Th1 clone and lung fibroblasts or splenic macrophages following immunoneutralization of MCP-1. In sep arate experiments, the selective inhibition of MCP-1 synthesis by lung fibroblasts and splenic macrophages using an MCP-1 antisense oligonuc leotide significantly enhanced the proliferation of CD4(+) T cells dur ing a 96-h coculture. Taken together, these data suggest that MCP-1 ex erts an immunomodulatory effect on CD4(+) T cell-derived IL-4 and IFN- gamma release and CD4(+) T cell proliferation during cell-to-cell inte ractions.