Modulation of platelet-derived growth factor B mRNA abundance in macrophages by colchicine and dibutyryl-cAMP.
Macrophage production of growth factors for fibroblasts, in particular platelet-derived growth factor B [PDGF(B)] and transforming growth factor-beta (TGF-beta), is thought to be central to the pathogenesis of pulmonary fibrosis. In a search for anti-inflammatory agents that might prevent this process, we asked whether colchicine might modulate the abundance of PDGF(B) and TGF-beta mRNA, as well as the mRNA of early growth response gene 2 (EGR2), in human macrophages. Colchicine caused a dose- and time-dependent increase in PDGF(B), but not TGF-beta or EGR2, mRNA in human macrophages derived from culture of peripheral blood monocytes. Similarly, colchicine caused an increase in PDGF(B) mRNA in human alveolar macrophages obtained from normal volunteers. Colchicine also caused an increase in PDGF(B) protein production by macrophages, as determined by enzyme-linked immunosorbent assay. Interferon-gamma further increased the PDGF(B) mRNA abundance in human alveolar but not monocyte-derived macrophages. The effect of coincubation with dibutyryl-cAMP (dBcAMP) was assessed in an attempt to prevent the colchicine-induced increase in PDGF(B) mRNA. dBcAMP alone resulted in no increase in PDGF(B) mRNA or alteration in TGF-beta mRNA but resulted in a reduction in EGR2 mRNA. When added with colchicine, dBcAMP completely abrogated the colchicine-induced increase in PDGF(B) mRNA but had little effect on TGF-beta mRNA. These data, showing that colchicine increased macrophage PDGF(B) mRNA in human macrophages and that this was prevented by coincubation with dBcAMP, lead us to speculate that colchicine may not be helpful in preventing the contribution of macrophage PDGF(B) gene activation to the pathogenesis of lung fibrosis. However, this effect of colchicine may be prevented by increasing intracellular cAMP in macrophages.
Wangoo
A
A
Department of Respiratory Medicine, St. Mary's Hospital Medical School, London, UK.
Haynes
A R
AR
Sutcliffe
S P
SP
Sorooshian
M
M
Shaw
R J
RJ
D003994:Bucladesine / Q000494:pharmacology*; D003078:Colchicine / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006684:HLA-DR Antigens / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000494:pharmacology; D008264:Macrophages / Q000502:physiology*; D016676:Macrophages, Alveolar / Q000502:physiology; D010982:Platelet-Derived Growth Factor / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta / Q000235:genetics
D006684:HLA-DR Antigens; D010982:Platelet-Derived Growth Factor; D011518:Proto-Oncogene Proteins; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D003994:Bucladesine; D007371:Interferon-gamma; D003078:Colchicine