MACROPHAGE FUNCTION IN MICE WITH A MUTATION AT THE MICROPHTHALMIA (MI) LOCUS

Microphthalmic (mi/mi) mice are unpigmented, osteopetrotic, mast cell deficient, and exhibit diminished gastric acid secretion and natural k iller cell activity, In order to assess the effect of this mutation on macrophage function, we studied superoxide (O-2(-)) and nitric oxide (NO) production, superoxide dismutase (SOD) activity, phagocytic capac ity, and tumor cell killing by peritoneal macrophages from mi/mi mice and normal (+/+) litter mates, Macrophages from mi/mi mice, upon activ ation with phorbol myristate acetate (PMA), generated significantly hi gher amounts of O-2(-) than did macrophages from their +/+ litter mate s, The phagocyte respiratory burst as assessed by nitroblue tetrazoliu m (NET) reduction assay also displayed a 2-fold enhancement in mi/mi m acrophages, The assay of SOD activity revealed significantly lower lev els in mi/mi macrophages than in the wild type, Furthermore, in compar ison with controls, macrophages from mi/mi mice demonstrated significa ntly higher levels of NO production and increased capacity to lyse tum or cells upon activation with lipopolysaccharide (LPS) or gamma-interf eron (IFN-gamma), The mi mutation, therefore, is associated with reduc ed macrophage SOD activity, increased O-2(-) and NO production, and en hanced capacity for tumor cell killing, The molecular mechanisms for t hese changes have not been identified.