(lung slices/influenza virus/endotoxin)

Pulmonary indoleamine 2,3-dioxygenase (indo- leamine: oxygen 2,3-oxidoreductase(decyclizing)) has been found to be induced (30- to 100-fold) in the mouse after a single intra- peritoneal administration of bacterial endotoxin (Yoshida, R. & Hayaishi, 0. (1978) Proc Natl. Acad. Sci. USA 75, 3998-4000) or during in vivo virus infection (Yoshida, R., Urade, Y., Tokuda, M. & Hayaishi, O. (1979) Proa Natl. Acad. Sci. USA 76, 4084-4086). In the present study, an in vitro system with mouse lung slices was developed in which bacterial endotoxin (5 /xg/ml) produced an induction (approximately 10-fold) of indoleamine 2,3-dioxygenase. The endotoxin was substituted by interferon from mouse L cells or mouse brain. The pulmonary enzyme activity increased almost linearly for 48 hr after addition of mouse interferon (104 units/ ml) to lung slices. Interferon from mouse L cells or mouse brain produced a 10- to 15-fold increase in the enzyme activity, whereas that from human leukocytes was all but ineffective. The effect also was observed using highly purified L-cell interferon, prepared by poly(U) affinity column chromatography. When interferon was treated either by heat, a-chymotrypsin, or anti-interferon serum, such increase in the enzyme activity was diminished essentially to the same extent as seen in the antiviral activity. The increase in the enzyme activity was blocked when actinomycin D or cyclohexi- mide was added to the slices before interferon treatment. These results suggest that the enzyme induction was produced by inter- feron and not by possible contaminants in the interferon preparations. Indoleamine 2,3-dioxygenase (indoleamine:oxygen 2,3-oxido- reductase (decyclizing)) (IDOase) is a hemoprotein (1) that ca- talyzes the incorporation of the superoxide anion as well as molecular oxygen (2, 3) into the pyrrole moiety of various in- doleamine derivatives (4, 5). The pulmonary IDOase is dra- matically induced (30- to 100-fold) in the mouse after a single intraperitoneal administration of bacterial endotoxin (lipopoly- saccharide (LPS)) (6) or during virus infection (7). To determine the precise mechanisms of IDOase induction, we developed an in vitro system with lung slices from mice and examined the ef- fects of various substances, including the superoxide anion, in- doleamines, and interferons, on the enzyme activity. We report herein that the IDOase activity was increased approximately 10- to 15-fold within 48 hr after the addition of mouse interferon (104 units/ml) to mouse lung slices. A species-specificity of interfer- ons and the effects of inhibitors of protein synthesis are pre- sented also.