TGFβ1 and TNFα secreted by mast cells stimulated via the FcεRI activate fibroblasts for high-level production of monocyte chemoattractant protein-1 (MCP-I)

Monocytes/macrophages usually make up the largest population of cells in the airways of allergic asthma patients and, as such, contribute substantially to the pathogenesis of this and other allergic diseases. In this report we address one mechanism by which monocytes can be recruited during allergic responses. We and others have shown previously that MCP-1 is important to monocyte infiltration of the tissues during allergic responses in mice and, independently, that mast cells activate fibroblasts to express type alpha 1(I)-collagen during such responses. We demonstrate herein that immunologically activated, but not quiescent mouse bone-marrow-derived mast cells release mediators which in turn activate primary cultures of embryonic dermal fibroblasts for high-level secretion of monocyte chemoattractant activities. We identify the CC chemokine MCP-1 as a major component of this activity. Anti-MCP-1 antibodies neutralized approximate to 80% of the monocyte chemoattractant activities secreted by such mast-cell-activated fibroblasts. Furthermore, our data implicate mast cell TGF beta and TNF alpha in this process. Depletion of TGF beta, TNF alpha, or both TGF beta and TNF alpha from the mediator pool secreted by mast cells activated via the Fc epsilon RI reduced the mast-cell-driven fibroblast MCP-1 response by 80 +/- 15, 56 +/- 11, or 82 +/- 5%, respectively. These data thus further delineate a mechanism by which fibroblasts are recruited into and participate in the mast cell-leukocyte cytokine cascades that orchestrate allergic responses. (C) 2000 Academic Press.