Eosinophil-fibroblast interactions. Granule major basic protein interacts with IL-1 and transforming growth factor-beta in the stimulation of 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-type cytokines, IL-6, IL-11, and leukemia inhibitory factor. Unstimulated fibroblasts did not produce substantial quantities of these cytokines, while IL-1 and TGF-beta(1) stimulated these cytokines in a potent fashion. MBP at doses < or = 44 micrograms/ml did not stimulate IL-6-type cytokine production. It did, however, interact in a synergistic, dose- and time-dependent fashion with rIL-1-alpha and TGF-beta(1) to further increase IL-6-type cytokine elaboration. These MBP-induced increases in cytokine production were associated with proportionate alterations in mRNA accumulation. In contrast, eosinophil-derived neurotoxin did not regulate fibroblast cytokine production, and MBP did not augment fibroblast granulocyte-macrophage-CSF, or type I collagen production, or fibroblast proliferation in this culture system. The effects of MBP could not be attributed to cell cytotoxicity or contaminants in the MBP preparations. They were, however, at least partially charge mediated, since heparin abolished the effects of MBP on IL-1-stimulated cells, and the surrogate cationic molecule poly-L-arginine mimicked the stimulatory effects of MBP on fibroblast IL-6-type cytokine elaboration. These studies demonstrate that MBP interacts in a synergistic fashion with rIL-1-alpha or TGF-beta(1) to further augment fibroblast IL-6-type cytokine production. They also demonstrate that this stimulation is pretranslationally mediated and due, in part, to the cationic nature of the MBP molecule. MBP regulation of fibroblast cytokine production may play an important role in the pathogenesis of eosinophilic disorders of the airway or other organs.
Rochester
C L
CL
Yale University School of Medicine, Department of Internal Medicine, Section of Pulmonary and Critical Care Medicine, New Haven, CT 06520, USA.
Ackerman
S J
SJ
Zheng
T
T
Elias
J A
JA
D001798:Blood Proteins / Q000008:administration & dosage* / Q000737:chemistry; D002412:Cations; D002450:Cell Communication; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004347:Drug Interactions; D047091:Eosinophil Granule Proteins; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007375:Interleukin-1 / Q000008:administration & dosage; D017370:Interleukin-11 / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D053605:Leukemia Inhibitory Factor; D008168:Lung / Q000166:cytology / Q000276:immunology* / Q000502:physiology; D008222:Lymphokines / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage; D012260:Ribonucleases; D016212:Transforming Growth Factor beta / Q000008:administration & dosage
D001798:Blood Proteins; D002412:Cations; D016207:Cytokines; D047091:Eosinophil Granule Proteins; D006131:Growth Inhibitors; D007375:Interleukin-1; D017370:Interleukin-11; D015850:Interleukin-6; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D012260:Ribonucleases