MODULATORY EFFECTS OF PKC ACTIVITY ON INCREASED 92-KDA GELATINASE SECRETION BY NEONATAL ALVEOLAR MACROPHAGES

We previously demonstrated that alveolar macrophages (AMs) from neonat al rats can secrete more 92-kDa gelatinase than AMs from adult rats. I n this study, we investigated the role of the protein kinase C (PKC) p athway in the transductional regulation of 92-kDa gelatinase secretion by rat AMs, and we also evaluated maturational changes in this role w ith increasing postnatal age. After AM stimulation by phorbol 12-myris tate 13-acetate (PMA), we observed a dose-dependent increase in gelati nase secretion that was significantly more marked in AMs from B-day-ol d rats than in AMs from adult rats and that was inhibited by the PKC i nhibitor calphostin C. Adenosine 3',5'-cyclic monophosphate mimetics o r concanavalin A failed to induce an increase in gelatinase secretion by AMs. Time-dependent variations in PKC activity after PMA stimulatio n differed significantly between B-day-old rats and adult rats; PKC ac tivity decreased in adult AMs (50%) but remained stable in 6-day-old A Ms. We therefore investigated age-related differences in the intracell ular proteolytic degradation of PKC, which is thought to be mediated b y calpains. Leupeptin, used as a calpain inhibitor, inhibited the decr ease in PKC activity after exposure of adult AMs to PMA and induced a greater than threefold increase in PMA-induced gelatinase secretion. C alpain activity was significantly lower in AM extracts from 6-day-old than from adult rats. The physiological implication of these developme ntal changes in 92-kDa gelatinase regulation was demonstrated by inves tigation of AMs from 1-day-old rats that showed a high level of sponta neous PKC-dependent gelatinase secretion coexisting with very low calp ain activity. We conclude that sustained PKC activity is a key factor in the increased gelatinase secretion by AMs seen during the postnatal period and is due, at least in part, to reduced PKC degradation.