DIFFERENTIAL REGULATION OF C-C CHEMOKINES DURING FIBROBLAST-MONOCYTE INTERACTIONS - ADHESION VS. INFLAMMATORY CYTOKINE PATHWAYS

THE cell-to-cell interactions during chronic inflammatory diseases lik ely contribute to leukocyte accumulation leading to increased patholog y and organ dysfunction, In particular, there is a paucity of informat ion relating to the maintenance of chronic fibrotic diseases, Using a lung fibroblast line and enriched monocyte populations, we have invest igated the activational events which contribute to the production of t wo C-C chemokines, macrophage inflammatory protein-1 alpha (MIP-1 alph a) and monocyte chemoattractant protein-1 (MCP-1), during fibroblast-m onocyte interactions. Neither the fibroblast cell line (16lu) nor isol ated monocytes alone produced significant levels of MIP-1 alpha or MCP -1. However, when isolated monocytes were layered onto 16lu fibroblast monolayers a significant increase in MIP-1 alpha and MCP-1 production was observed. The use of fixed cell populations indicated that the MI P-1 alpha was derived from monocytes and MCP-1 from both cell populati ons, To examine the molecules which were required for chemokine produc tion during the interaction, specific antibodies were used in the co-c ultures. Blocking beta 3-integrin interactions significantly inhibited MIP-1 alpha production. In contrast, beta-integrin interactions had n o effect on the MCP-1 production, while, neutralization of TNF signifi cantly decreased MCP-1 production during the co-culture, These data in dicate that fibroblast-monocyte interactions induce chemokine producti on through different mechanisms and a combination of these responses m ay contribute to the maintenance of the mononuclear cell accumulation during disease progression.