EFFECTS OF SERINE-PROTEASE INHIBITOR, TAME, ON IL-1-BETA IN LPS-STIMULATED HUMAN MONOCYTES - RELATIONSHIP BETWEEN SYNTHESIS AND RELEASE OF A 33-KDA PRECURSOR AND THE 17-KDA BIOLOGICALLY-ACTIVE SPECIES

LPS stimulation of human monocytes in vitro induced release of the 17- kDa mature IL-1beta (mIL-1beta) but did not result in release of precu rsor IL-1beta (pIL-1beta). In contrast, the presence of a serine prote ase inhibitor, Nalpha-(p-toluene sulfonyl)-L-arginine methyl ester (TA ME; 10 mM) for 6 or 18 h was associated with the LPS-stimulated releas e of the 33-kDa pIL-1beta as well. These effects were initially discer ned from observations that the fraction of the total IL-1beta produced (as detected by ELISA) that was released from monocytes increased in the presence of TAME, and immunoblot assays confirmed that this fracti on was predominantly 33-kDa IL-1beta. A global decrease in monocyte pr otein synthesis was also observed after prolonged (18-h) exposure to T AME and was associated with a decrease in IL-1beta synthesis, predomin antly affecting 31-kDa pIL-1beta, and a dose-dependent inhibition of T NF-alpha production. Parallel examination of lactate dehydrogenase (LD H) release indicated that pIL-1beta release was unrelated to cell lysi s. These results demonstrate that TAME-inhibitable serine proteases ar e probably involved in the production and eventual proteolysis of the 33-kDa pIL-1beta in situ but are probably not mechanistically related to either maturation of the IL-1beta molecule or signaling of IL-1beta release. IL-1beta release appears to be dependent on the amount of to tal IL-1beta synthesized. Serine proteolysis may constitute a degradat ive pathway for excess precursor, which, if interfered with, could res ult in release of the higher-molecular-weight forms of IL-1beta.