INTERLEUKIN-1-BETA (IL-1-BETA) AND THE IL-1-BETA-ALPHA(2)-MACROGLOBULIN COMPLEX UP-REGULATE THE PLATELET-DERIVED GROWTH-FACTOR ALPHA-RECEPTOR ON RAT PULMONARY FIBROBLASTS

Fibroblasts are the primary proliferating cell type in pulmonary fibrosis. We previously showed that inorganic, fibrogenic particles alter the platelet-derived growth factor (PDGF) receptor system on rat lung fibroblasts (Bonner, J. C., et al, 1993, J. Clin. Invest 92:425-430). In lung fibroblasts, PDGF is the most potent proliferative cytokine, and the responses to PDGF isoforms depend on the relative amounts of two PDGF receptors (PDGF-R alpha and PDGF-R beta). Interleukin 1 beta (IL-1 beta) production by lung macrophages is increased following exposure to fibrogenic particles. We have examined the role of IL-1 beta in regulating the lung fibroblast PDGF receptor system. IL-1 beta induced a 10-fold increase in the number of binding sites for [I-125]PDGF-AA, caused a 2-fold increase in affinity of [I-125]PDGF-AB, but it had no effect on [I-125]PDGF-BB binding. PDGF-R alpha gene expression was increased 5-fold after 4 h of IL-1 beta treatment. IL-1 beta increased the proliferative and chemotactic response to PDGF isoforms in the following order of potency: AA > AB > BB. IL-1 beta was tested for its ability to cause increased [I-125]PDGF-AA binding when complexed to its binding protein, alpha(2)-macroglobulin (alpha(2)M). IL-1 beta bound covalently to fast methylamine-activated alpha(2)M (alpha(2)M-MA). IL-1 beta-alpha(2)M-MA or alpha(2)M-MA alone possessed minimal activity for inducing an increase in [I-125]PDGF-AA binding. However, treatment of the IL-1 beta-alpha(2)M-MA complex with thioredoxin, which released bioactive IL-1 beta that was covalently bound to alpha(2)M, maximally increased [I-125]PDGF-AA binding to the same extent as free IL-1 beta. These results indicate that the fibroblast response to PDGF isoforms is modulated by a complex interaction involving IL-1 beta, alpha(2)M, and thioredoxin, all of which are produced in vivo by activated macrophages.