Synthesis of PGE2, collagenase and tissue factor by fibroblast substrains: substrains are differentially activated for different metabolic products.

Metabolic heterogeneity has previously been demonstrated for cloned fibroblast populations. It is unclear whether a "high producer" or "activated" phenotype for one cell product reflects general metabolic activation or whether activated phenotypes for different metabolic markers segregate independently among cloned populations. We examined human foreskin fibroblast substrains, isolated by limiting dilution cloning, for heterogeneity in biosynthesis of PGE2 and collagenase (stimulated by Interleukin 1-containing mononclear cell supernates), and tissue factor. Synthesis of these products varied 5- to 10-fold among 16 substrains isolated from two parent lines (AT and WB). Metabolic phenotypes (high versus low levels of synthesis) were stable for the substrains over multiple weeks of culture. In neither group of substrains was there a correlation between levels of stimulated PGE synthesis and stimulated collagenase synthesis (r = -0.24 and 0.29 for AT and WB substrains, respectively). Similarly, tissue factor generation did not correlate with either PGE production (r = 0.12 and -0.38 for AT and WB substrains, respectively) or collagenase synthesis (r = 0.17 and 0.21 for AT and WB substrains, respectively). The discordance between high producer phenotypes for the different products was observed even when all three products were measured in the same culture. Activated phenotypes for different metabolic markers thus appear to segregate among cells independently. The process of connective tissue activation by immune cell-derived mediators may depend on the constituent makeup of the responding connective tissue cell population.