Growth factors, lipid mediators and effector cells

Hematopoetic growth factors stimulate the proliferation of leukocyte precursors in bone marrow cultures, but some also augment the responsiveness of mature effector cells. For example, granulocyte-macrophage colony-stimulating factor (GM-CSF) enhances superoxide production and cytotoxicity of neutrophils stimulated by diverse agonists. We show that preexposure of neutrophils to GM-CSF is absolutely required for the induction of leukotriene B4 and platelet-activating factor (PAF) synthesis by a soluble agonist, C5a or N-formyl-methionyl-leucine-phenylalanine (FMLP). Lipid mediator synthesis occurs very rapidly after triggering with the second signal, and under identical conditions superoxide release is enhanced. Interleukin-3 (IL-3), another hematopoetic growth factor, enhances granule release and more profoundly leukotriene C4 (LTC4) synthesis in basophils stimulated by immunoglobulin-E (IgE)-dependent or -independent agonists. Sequential stimulation with IL-3 and C5a results in the production of large quantities of LTC4, while neither factor alone induces the release of lipid mediators. We conclude that a major function of these cytokines is to allow lipid mediator synthesis in effector cells after triggering with agonists which by themselves do not induce the production of bioactive lipids. We also propose that lipoxygenase metabolites and PAF represent an autocrine response amplification pathway in effector cells which might explain the enhanced responsiveness of cells primed by these cytokines.