Regulation of macrophage-derived fibroblast growth factor release by arachidonate metabolites.

The macrophage is a source of many mediators with direct and indirect fibrogenic potential. In this study, release of macrophage-derived fibroblast growth factor (MDGF) activity by murine peritoneal macrophages is examined with regard to its regulation by arachidonate metabolites. Upon stimulation with 10 micrograms/ml lipopolysaccharide (LPS), resident peritoneal macrophages from CBA/J mice released MDGF activity into media rapidly, reaching maximal levels in approximately 1 h. Lysates of these stimulated cells also revealed significantly increased cell-associated MDGF activity, composing 45% of the total assayable activity. This activity, as assayed by radioactive thymidine incorporation by primary cultures of rat lung fibroblasts, was separable from interleukin-1 (IL-1) activity by reverse phase high performance liquid chromatography (HPLC). Furthermore, purified murine IL-1 had no MDGF activity in this assay system. This stimulated MDGF release was enhanced by the cyclooxygenase inhibitors indomethacin, ibuprofen, and aspirin at micromolar concentrations, but inhibited in a dose-dependent manner by prostaglandin E2 (PGE2). On the other hand, nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor was inhibitory at 0.1 and 0.4 microM but not at 2.5 microM. Zymosan-stimulated macrophages also markedly increased MDGF release, albeit with a different time course which was characterized by a delay of approximately 7 h before peak levels were attained. Such stimulation, which is known to cause increased lipoxygenase activity, was also inhibited by 0.5 microM NDGA. In contrast, the lipoxygenase pathway products leukotrienes B4 (LTB4) and C4 (LTC4) stimulated MDGF release in a dose-dependent (10(-10)-10(-8) M) manner, with LTC4 being more potent on a per unit dose basis. Stimulation by LTC4 was inhibited by the putative leukotriene receptor antagonist, FPL55712, while LTD4 and LTE4 did not stimulate MDGF release, thus suggesting the mediation of this effect by specific LTC4 receptors. These data suggest also that products of the cyclooxygenase and lipoxygenase pathways are potentially important both as exogenous (ie, derived from cells other than the macrophage itself) and auto- or self-regulators of macrophage MDGF release. This, in turn, implies that cyclooxygenase products are antifibrogenic and important in maintaining or returning to the quiescent or normal state, whereas the lipoxygenase products are profibrogenic and important in induction of fibrosis or wound-healing and tissue repair. Any alteration in the balance between these two pathways may result in either a desirable or a harmful outcome.