EOSINOPHIL-FIBROBLAST INTERACTIONS - GRANULE MAJOR BASIC-PROTEIN INTERACTS WITH IL-1 AND TRANSFORMING GROWTH-FACTOR-BETA IN THE STIMULATIONOF LUNG FIBROBLAST IL-6-TYPE CYTOKINE PRODUCTION

To test the hypothesis that eosinophil major basic protein (MBP) is an important regulator of fibroblast effector function, we characterized the effects of MBP on human lung fibroblast production of the IL-6-ty pe cytokines, IL-6, IL-11, and leukemia inhibitory factor. Unstimulate d fibroblasts did not produce substantial quantities of these cytokine s, while IL-1 and TCF-beta(1), stimulated these cytokines in a potent fashion. MBP at doses less than or equal to 44 mu g/ml did not stimula te IL-6-type cytokine production. It did, however, interact in a syner gistic, dose- and time-dependent fashion with rIL-1-alpha and TGF-beta (1) to further increase IL-6-type cytokine elaboration. These MBP-indu ced increases in cytokine production were associated with proportionat e alterations in mRNA accumulation, in contrast, eosinophil-derived ne urotoxin did not regulate fibroblast cytokine production, and MBP did not augment fibroblast granulocyte-macrophage-CSF, or type 1 collagen production, or fibroblast proliferation in this culture system. The ef fects of MBP could not be attributed to cell cytotoxicity or contamina nts in the MBP preparations. They were, however, at least partially ch arge mediated, since heparin abolished the effects of MBP on IL-1-stim ulated cells, and the surrogate cationic molecule poly-L-arginine mimi cked the stimulatory effects of MBP on fibroblast IL-6-type cytokine e laboration. These studies demonstrate that MBP interacts in a synergis tic fashion with rIL-1-alpha or TCF-beta(1) to further augment fibrobl ast IL-6-type cytokine production. They also demonstrate that this sti mulation is pretranslationally mediated and due, in part, to the catio nic nature of the MBP molecule. MBP regulation of fibroblast cytokine production may play an important role in the pathogenesis of eosinophi lic disorders of the airway or other organs.