SYNERGISTIC INDUCTION OF MCP-1 AND MCP-2 BY IL-1-BETA AND INTERFERONSIN FIBROBLASTS AND EPITHELIAL-CELLS

Monocyte chemotactic protein (MCP)-1 and MCP-2, two closely related CC chemokines, are important mediators of monocyte and lymphocyte migrat ion, These chemokines are secreted by various normal cell types, inclu ding fibroblasts, epithelial cells, and leukocytes, as well as by tumo r cells, After stimulation with different cytokines and cytokine induc ers the MCP-2 production levels are always lower than those of MCP-1, In human diploid fibroblasts cytokines differentially regulate chemoki ne induction, interleukin (IL)-1 beta and interferon (IFN)-gamma being potent stimuli of MCP-1 and MCP-2, respectively. Co-stimulation of fi broblasts by 10 U/mL IL-1 beta and 20 ng/mL IFN-gamma resulted in a sy nergistic induction of MCP-2, whereas the combined effect on MCP-1 and IL-6 production was rather additive, These findings were confirmed at the mRNA level by Northern blot analysis, In contrast, in human MG-63 fibroblastoid cells and HEp-2 epithelial cells, selected for their po or responsiveness to IL-1 beta and IFN-gamma, MCP-2 as well as MCP-1 a nd IL-6 were synergistically induced, yielding protein levels that wer e increased 3- to 30-fold above the additive levels, When IFN-beta was used as a co-stimulant of IL-1 beta, a similar synergistic induction of MCP-1 and MCP-2 was measured both at the protein and the mRNA level , It call be concluded that, when synergy occurred, the MCP-1 and MCP- 2 expression levels reached a comparable maximum, indicative for an eq ual contribution of these chemokines in normal and pathological condit ions.