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 fibro sis. We previously showed that inorganic, fibrogenic particles alter t he platelet-derived growth factor (PDGF) receptor system on rat lung f ibroblasts (Bonner, J. C., et al, 1993, J. Clin. Invest 92:425-430). I n lung fibroblasts, PDGF is the most potent proliferative cytokine, an d 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 exposur e to fibrogenic particles. We have examined the role of IL-1 beta in r egulating 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 inc reased 5-fold after 4 h of IL-1 beta treatment. IL-1 beta increased th e proliferative and chemotactic response to PDGF isoforms in the follo wing order of potency: AA > AB > BB. IL-1 beta was tested for its abil ity to cause increased [I-125]PDGF-AA binding when complexed to its bi nding protein, alpha(2)-macroglobulin (alpha(2)M). IL-1 beta bound cov alently to fast methylamine-activated alpha(2)M (alpha(2)M-MA). IL-1 b eta-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 bi oactive IL-1 beta that was covalently bound to alpha(2)M, maximally in creased [I-125]PDGF-AA binding to the same extent as free IL-1 beta. T hese results indicate that the fibroblast response to PDGF isoforms is modulated by a complex interaction involving IL-1 beta, alpha(2)M, an d thioredoxin, all of which are produced in vivo by activated macropha ges.