COINDUCTION OF ARGINASE AND NITRIC-OXIDE SYNTHASE IN MURINE MACROPHAGES ACTIVATED BY LIPOPOLYSACCHARIDE

In view of studies showing that not only nitric oxide synthase (NOS) a ctivity but arginase activity is induced in rodent macrophages by lipo polysaccharide (LPS), the objective of this study was to investigate t he co-induction of these two enzymes and to ascertain whether common m echanisms are involved. RAW 264.7 cells were activated by 2 mu g LPS/m l and incubated for up to 48 hr. Inducible NOS (iNOS) and inducible ar ginase II (AII) activities were monitored, respectively, by measuring NO2-/NO3- accumulation in cell culture media and formation of urea (as CO2) from L-arginine by cell lysates. AII activity increased linearly up to at least 48 hr, whereas NO2-/NO3- formation reached a plateau w ell before 48 hr. Immunoprecipitation experiments revealed that AII ac counted for 90-100% of arginase activity in LPS-activated macrophages. The inhibitor of NF-kappa B activation, pyrrolidine dithiocarbamate, inhibited the induction of iNOS but not AII. Moreover, whereas IFN-gam ma caused iNOS induction, AII induction was nearly abolished by IFN-ga mma, perhaps by inhibiting transcription of the These observations ind icate that co-induction of iNOS and AII occurs by distinct transcripti onal mechanisms, AII induction could diminish NO production by decreas ing L-arginine availability, and IFN-gamma can prevent AII induction. (C) 1995 Academic Press, Inc.